WO2022033567A1 - 苯并咪唑类衍生物、其制备方法及医药用途 - Google Patents

苯并咪唑类衍生物、其制备方法及医药用途 Download PDF

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WO2022033567A1
WO2022033567A1 PCT/CN2021/112386 CN2021112386W WO2022033567A1 WO 2022033567 A1 WO2022033567 A1 WO 2022033567A1 CN 2021112386 W CN2021112386 W CN 2021112386W WO 2022033567 A1 WO2022033567 A1 WO 2022033567A1
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halogen
alkyl
optionally substituted
deuterium
hydrogen
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PCT/CN2021/112386
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English (en)
French (fr)
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李文明
刘宁
刘彪
刘浩淼
余健
邹昊
祝伟
李正涛
张瑱
李云飞
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上海拓界生物医药科技有限公司
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Priority to KR1020237007672A priority Critical patent/KR20230051209A/ko
Priority to JP2023507819A priority patent/JP2023536986A/ja
Priority to CN202180049784.5A priority patent/CN115835867A/zh
Priority to CA3187092A priority patent/CA3187092A1/en
Priority to US18/020,055 priority patent/US20230250095A1/en
Priority to BR112023001924A priority patent/BR112023001924A2/pt
Priority to EP21855617.3A priority patent/EP4198034A4/en
Publication of WO2022033567A1 publication Critical patent/WO2022033567A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present disclosure relates to the field of medicine, in particular to a new class of benzimidazole derivatives, a preparation method thereof, and applications in medicine.
  • P2X receptors are a family of cation-permeable ligand-gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP). They belong to a larger family of receptors called purinergic receptors. P2X receptors are present in a variety of organisms, including humans, mice, rats, rabbits, chickens, zebrafish, bullfrogs, flukes, and amoeba. Seven independent genes encoding P2X subunits have been identified and named P2X1 to P2X7. Different subunits exhibit different sensitivities to purinergic agonists and antagonists.
  • P2X3 receptors have 4 ATP binding sites on a single subunit, consisting of 2 transmembrane domains, N-terminal and C-terminal located in the cell, and a conserved sequence located in the extracellular loop structure.
  • the high expression of P2X3 receptors was found in specific small and medium diameter neurons related to nociceptive information.
  • P2X3 receptors are also involved in the transmission of some non-nociceptive sensations. It has been confirmed that the P2X3 receptor is involved in bladder sensory function and is a key receptor-mediated bladder sensory signal, expressed in the bladder mucosal tissue rich in sensory nerve fibers. P2X3 is also expressed in the sensory nerve fibers of the pharyngeal mucosa, which is related to the conduction and formation of taste.
  • P2X3 receptor When the body is injured or nerve damage, a large amount of ATP is released, which activates the P2X3 receptor in the presynaptic membrane, causing a large amount of Ca2 + influx, and the increase in the intracellular calcium concentration activates protein kinase A (PKA), protein kinase C (protein kinase A). kinase C, PKC), which phosphorylates PKA and PKC, and at the same time promotes the release of glutamate, which further activates NMDA receptors, resulting in the generation of excitatory postsynaptic currents and central sensitization.
  • PKA protein kinase A
  • PKC protein kinase C
  • MK-7264 is a P2X3 receptor activity antagonist with IC50 values of ⁇ 30nM and 100-250nM for human homologous recombination hP2X3 and hP2X2/3, respectively, and its use in the treatment of chronic cough patients has been clinically Phase III.
  • the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an isomer thereof,
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 -C alkyl optionally substituted with halogen or deuterium C 6 alkoxy;
  • R 2 is each independently selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 optionally substituted with halogen or deuterium -C 6 alkoxy;
  • R3 and R4 are each independently selected from hydrogen, halogen, and C1 - C4 alkyl optionally substituted with halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form optionally substituted with halogen A C 3 -C 6 cycloalkylene group, or R 3 and R 4 on adjacent carbon atoms together form a C 3 -C 8 cycloalkane optionally substituted by halogen;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, C 3 -C 6 cycloalkyl optionally substituted by halogen or cyano, optionally substituted by halogen or cyano Heterocyclyl, C1 - C6alkoxy optionally substituted with halogen or cyano, and amino optionally substituted with alkyl;
  • R 6 is each independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, and C 1 -C 6 alkyl optionally substituted with halogen or deuterium;
  • R 7 and R 8 are each independently selected from:
  • R 9 and R 10 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 -C 8 cyclohydrocarbyl, or R 9 and R 10 together with the nitrogen atom to which it is commonly attached forms a 4-6 membered heterocyclic group optionally selected from halogen, hydroxy, cyano, C 1 -C 6 haloalkyl and C 1 -C 6 alkane is substituted with one or more substituents of the radical;
  • R' is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and heteroaryl; and in In, when p is 0, the combination of R 9 and R 10 is not hydrogen and methyl;
  • Heterocyclyl and heteroaryl each of which is optionally selected from one or more of oxo, halogen, hydroxy, carbonyl, C1 - C6 alkyl and cyano substituted with one or more substituents, the C 1 -C 6 alkyl optionally substituted with one or more halogens; and
  • R 11 is selected from C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, aryl group, heteroaryl group, C 3 -C 8 cycloalkyl group, heterocyclic group, C 1 -C 6 cyanoalkane group group, C 3 -C 8 cycloalkyloxy and amino optionally substituted with C 1 -C 6 alkyl; or
  • R7 and R8 together with the atoms to which they are commonly attached form an optionally substituted aromatic or non-aromatic heterocycle
  • X is selected from oxygen atoms, -NH- and methylene optionally selected from halogen, C3 - C8 cycloalkyl, C3 - C6 cycloalkylene and C1 - C6 alkane is substituted with one or more substituents of the radical;
  • n is an integer from 1 to 3;
  • n is an integer of 1-4.
  • R 7 and R 8 are each independently selected from:
  • R 9 and R 10 are each independently selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 3 -C 6 cyclohydrocarbyl, or R 9 and R 10 together with the nitrogen atom to which it is commonly attached forms a 4-6 membered heterocyclic group optionally substituted with one or more substituents selected from halogen, hydroxy and C 1 -C 3 alkyl;
  • R ' is selected from hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cyclohydrocarbyl, aryl and heteroaryl; and in In, when p is 0, the combination of R 9 and R 10 is not hydrogen and methyl;
  • 4-6 membered heterocyclic or heteroaryl optionally selected from oxo, halogen, hydroxy, carbonyl, C 1 -C 3 alkyl and cyano substituted with one or more substituents, the C1 - C3 alkyl group may be optionally substituted with one or more halogens;
  • R 11 is selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, 5-6 membered aryl or heteroaryl, 3-8 membered cyclic hydrocarbon group, 3-8 membered heterocyclic group, C 1 -C3cyanoalkyl, C3 - C6cyclohydrocarbyloxy and amino optionally substituted by C1 - C3alkyl .
  • R 7 is a 4-6 membered heterocyclyl or heteroaryl group optionally selected from oxo, halogen, hydroxy, carbonyl, C 1 -C 3 alkyl and cyano groups are substituted with one or more substituents, and the C 1 -C 3 alkyl group is optionally substituted with one or more halogens; and
  • R8 is selected from hydrogen, deuterium, halogen, cyano, and C1 - C3 alkyl substituted with one or more halogens.
  • R8 is selected from hydrogen, deuterium, halogen, cyano, and C1 - C3 alkyl substituted with one or more halogens.
  • R8 is selected from hydrogen, deuterium, halogen, cyano, and C1 - C3 alkyl substituted with one or more halogens.
  • R 1 is selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 -C 6 optionally substituted with halogen or deuterium alkoxy;
  • R 2 is each independently selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 optionally substituted with halogen or deuterium -C 6 alkoxy;
  • R3 and R4 are each independently selected from hydrogen, halogen, and C1 - C4 alkyl optionally substituted with halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form optionally substituted with halogen A C 3 -C 6 cycloalkylene group, or R 3 and R 4 on adjacent carbon atoms together form a C 3 -C 8 cycloalkane optionally substituted by halogen;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, C 3 -C 6 cycloalkyl optionally substituted by halogen or cyano, optionally substituted by halogen or cyano Heterocyclyl, C1 - C6alkoxy optionally substituted with halogen or cyano, and amino optionally substituted with alkyl;
  • R 6 is each independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, and C 1 -C 6 alkyl optionally substituted with halogen or deuterium;
  • R 7 and R 8 together with the atoms to which they are commonly attached form a 3-12 membered aromatic or non-aromatic heterocyclic ring, which is monocyclic or bicyclic, optionally selected from C 1 -C 6 alkylamides , halogen, oxo, optionally substituted with one or more substituents of halogen-substituted C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
  • X is selected from oxygen atoms, -NH- and methylene optionally selected from halogen, C3 - C8 cycloalkyl, C3 - C6 cycloalkylene and C1 - C6 alkane is substituted with one or more substituents of the radical;
  • n is an integer from 1 to 3;
  • n is an integer of 1-4.
  • R 7 and R 8 together with the atoms to which they are commonly attached form a 3-12 membered non-aromatic heterocycle
  • the heterocycle is monocyclic or bicyclic
  • said heterocycle is optionally selected from C 1 -C 6 alkylamide, halogen, oxo, optionally halogen substituted C 1 -C 6 alkyl and one or more substituents of C 1 -C 6 alkoxy.
  • R 7 and R 8 together with the atoms to which they are commonly attached form a 4-8 membered non-aromatic heterocycle
  • the heterocycle is monocyclic or bicyclic
  • said heterocycle is optionally selected from C 1 -C 3 alkylamide, halogen, oxo, optionally halogen substituted C 1 -C 3 alkyl and one or more substituents of C 1 -C 3 alkoxy.
  • R 1 is selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 -C 6 optionally substituted with halogen or deuterium alkoxy;
  • R 2 is each independently selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 optionally substituted with halogen or deuterium -C 6 alkoxy;
  • R3 and R4 are each independently selected from hydrogen, halogen, and C1 - C4 alkyl optionally substituted with halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form optionally substituted with halogen A C 3 -C 6 cycloalkylene group, or R 3 and R 4 on adjacent carbon atoms together form a C 3 -C 8 cycloalkane optionally substituted by halogen;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, C 3 -C 6 cycloalkyl optionally substituted by halogen or cyano, optionally substituted by halogen or cyano Heterocyclyl, C1 - C6alkoxy optionally substituted with halogen or cyano, and amino optionally substituted with alkyl;
  • R 6 is each independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, and C 1 -C 6 alkyl optionally substituted with halogen or deuterium;
  • R7 is p is selected from 0, 1 and 2
  • R 9 and R 10 are each independently selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 3 -C 6 cyclohydrocarbyl, or R 9 and R 10 together with the nitrogen atom to which it is commonly attached forms a 4-6 membered heterocyclic group optionally substituted with one or more substituents selected from halogen, hydroxy and C 1 -C 3 alkyl;
  • R8 is selected from hydrogen, deuterium, halogen, cyano and C1 - C3 alkyl substituted with one or more halogens;
  • X is selected from oxygen atoms, -NH- and methylene optionally selected from halogen, C3 - C8 cycloalkyl, C3 - C6 cycloalkylene and C1 - C6 alkane is substituted with one or more substituents of the radical;
  • n is an integer from 1 to 3;
  • n is an integer of 1-4.
  • R7 is p is 0 or 1
  • R 9 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 3 -C 6 cyclohydrocarbyl
  • R 10 is hydrogen, or R 9 and R 10 together
  • the attached nitrogen atoms together form a 4-6 membered heterocyclyl group optionally substituted with one or more halogens;
  • R8 is selected from hydrogen, deuterium and halogen.
  • R 1 is selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 -C 6 optionally substituted with halogen or deuterium alkoxy;
  • R 2 is each independently selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 optionally substituted with halogen or deuterium -C 6 alkoxy;
  • R3 and R4 are each independently selected from hydrogen, halogen, and C1 - C4 alkyl optionally substituted with halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form optionally substituted with halogen A C 3 -C 6 cycloalkylene group, or R 3 and R 4 on adjacent carbon atoms together form a C 3 -C 8 cycloalkane optionally substituted by halogen;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, C 3 -C 6 cycloalkyl optionally substituted by halogen or cyano, optionally substituted by halogen or cyano Heterocyclyl, C1 - C6alkoxy optionally substituted with halogen or cyano, and amino optionally substituted with alkyl;
  • R 6 is each independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, and C 1 -C 6 alkyl optionally substituted with halogen or deuterium;
  • R7 is p is selected from 0, 1 and 2
  • R 9 and R 10 are each independently selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 3 -C 6 cyclohydrocarbyl, or R 9 and R 10 together with the nitrogen atom to which it is commonly attached forms a 4-6 membered heterocyclic group optionally substituted with one or more substituents selected from halogen, hydroxy and C 1 -C 3 alkyl
  • R ' is selected from hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cyclohydrocarbyl, aryl and heteroaryl;
  • R8 is selected from hydrogen, deuterium, halogen, cyano and C1 - C3 alkyl substituted with one or more halogens;
  • X is selected from oxygen atoms, -NH- and methylene optionally selected from halogen, C3 - C8 cycloalkyl, C3 - C6 cycloalkylene and C1 - C6 alkane is substituted with one or more substituents of the radical;
  • n is an integer from 1 to 3;
  • n is an integer of 1-4.
  • R7 is p is 0 or 1
  • R 9 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 3 -C 6 cyclohydrocarbyl
  • R 10 is hydrogen, or R 9 and R 10 together
  • the attached nitrogen atoms together form a 4-6 membered heterocyclyl group optionally substituted with one or more halogens
  • R' is selected from hydrogen, C1 - C3 alkyl, C3 - C6 ring Hydrocarbyl, aryl and heteroaryl groups; and
  • R8 is selected from hydrogen, deuterium and halogen.
  • R 1 is selected from hydrogen, deuterium, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 2 are each independently selected from hydrogen, deuterium, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R3 and R4 are each independently hydrogen or halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form a C3 - C6 cycloalkylene group optionally substituted with halogen, or a C3 - C6 cycloalkylene group on adjacent carbon atoms R3 and R4 together form an optionally halogen - substituted C3 - C8 cycloalkane;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, C 3 -C 6 cycloalkyl optionally substituted by halogen or cyano, optionally substituted by halogen or cyano Heterocyclyl, C1 - C6alkoxy optionally substituted with halogen or cyano, and amino optionally substituted with alkyl;
  • R 6 is each independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, and C 1 -C 6 alkyl optionally substituted with halogen or deuterium;
  • R 7 and R 8 are each independently selected from:
  • R 9 and R 10 are each independently selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 3 -C 6 cyclohydrocarbyl, or R 9 and R 10 together with the nitrogen atom to which it is commonly attached forms a 4-6 membered heterocyclic group optionally substituted with one or more substituents selected from halogen, hydroxy and C 1 -C 3 alkyl;
  • R ' is selected from hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cyclohydrocarbyl, aryl and heteroaryl; and in In, when p is 0, the combination of R 9 and R 10 is not hydrogen and methyl;
  • Heterocyclyl and heteroaryl each of which is optionally selected from one or more of oxo, halogen, hydroxy, carbonyl, C1 - C6 alkyl and cyano substituted with one or more substituents, the C 1 -C 6 alkyl optionally substituted with one or more halogens; and
  • R 11 is selected from C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, aryl group, heteroaryl group, C 3 -C 8 cycloalkyl group, heterocyclic group, C 1 -C 6 cyanoalkane group group, C 3 -C 8 cycloalkyloxy and amino optionally substituted with C 1 -C 6 alkyl; or
  • R7 and R8 together with the atoms to which they are commonly attached form an optionally substituted aromatic or non-aromatic heterocycle
  • X is selected from oxygen atoms, -NH- and methylene optionally selected from halogen, C3 - C8 cycloalkyl, C3 - C6 cycloalkylene and C1 - C6 alkane is substituted with one or more substituents of the radical;
  • n is an integer from 1 to 3;
  • n is an integer of 1-4.
  • R 5 is C 1 -C 6 alkyl optionally substituted with halogen or cyano or C 1 -C 6 alkoxy optionally substituted with halogen or cyano;
  • R 6 is each independently selected from hydrogen, deuterium, halogen and cyano
  • n is an integer of 1-4.
  • R 1 is selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halo or deuterium, and halo;
  • R 2 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R3 and R4 are each independently hydrogen or halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form a C3 - C6 cycloalkylene group optionally substituted with halogen ;
  • R 5 is C 1 -C 6 alkyl or C 1 -C 6 alkoxy
  • Each R is independently selected from hydrogen, deuterium, halogen and cyano ;
  • R 7 and R 8 are each independently selected from:
  • R 9 and R 10 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 -C 8 cyclohydrocarbyl, or R 9 and R 10 together with the nitrogen atom to which it is commonly attached forms a 4-6 membered heterocyclyl group, wherein: the heterocyclyl group is optionally selected from halogen, hydroxy, cyano, C 1 -C 6 haloalkyl and C 1 -C 6 is substituted with one or more substituents of the alkyl group; and in In, when p is 0, the combination of R 9 and R 10 is not hydrogen and methyl;
  • Heterocyclyl and heteroaryl each of which is optionally selected from one or more of oxo, halogen, hydroxy, carbonyl, C1 - C6 alkyl and cyano substituted with one or more substituents, the C 1 -C 6 alkyl optionally substituted with one or more halogens; and
  • R 11 is selected from C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, aryl group, heteroaryl group, C 3 -C 8 cycloalkyl group, heterocyclic group, C 1 -C 6 cyanoalkane group group, C 3 -C 8 cycloalkyloxy and amino optionally substituted with C 1 -C 6 alkyl; or
  • R7 and R8 together with the atoms to which they are commonly attached form an optionally substituted aromatic or non-aromatic heterocycle
  • n is an integer from 1 to 3;
  • n is an integer of 1-4.
  • R 1 is selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 -C 6 optionally substituted with halogen or deuterium alkoxy;
  • R 2 is each independently selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 optionally substituted with halogen or deuterium -C 6 alkoxy;
  • R3 and R4 are each independently selected from hydrogen, halogen, and C1 - C4 alkyl optionally substituted with halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form optionally substituted with halogen C 3 -C 6 cycloalkylene group, or R 3 and R 4 on adjacent carbon atoms together form C 3 -C 8 cycloalkane optionally substituted by halogen;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, C 3 -C 6 cycloalkyl optionally substituted by halogen or cyano, optionally substituted by halogen or cyano Heterocyclyl, C1 - C6alkoxy optionally substituted with halogen or cyano, and amino optionally substituted with alkyl;
  • R 6 is each independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, and C 1 -C 6 alkyl optionally substituted with halogen or deuterium;
  • R 7 is the following group optionally substituted with one or more substituents selected from methyl, fluorine, chlorine, halomethyl and cyano:
  • R8 is selected from hydrogen, deuterium, halogen, cyano and C1 - C3 alkyl substituted with one or more halogens;
  • X is selected from oxygen atoms, -NH- and methylene optionally selected from halogen, C3 - C8 cycloalkyl, C3 - C6 cycloalkylene and C1 - C6 alkane is substituted with one or more substituents of the radical;
  • n is an integer from 1 to 3;
  • n is an integer of 1-4.
  • R 1 is selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 -C 6 optionally substituted with halogen or deuterium alkoxy;
  • R 2 is each independently selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 optionally substituted with halogen or deuterium -C 6 alkoxy;
  • R3 and R4 are each independently selected from hydrogen, halogen, and C1 - C4 alkyl optionally substituted with halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form optionally substituted with halogen A C 3 -C 6 cycloalkylene group, or R 3 and R 4 on adjacent carbon atoms together form a C 3 -C 8 cycloalkane optionally substituted by halogen;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, C 3 -C 6 cycloalkyl optionally substituted by halogen or cyano, optionally substituted by halogen or cyano Heterocyclyl, C1 - C6alkoxy optionally substituted with halogen or cyano, and amino optionally substituted with alkyl;
  • Heterocycle A is selected from the following structures:
  • Each R is independently selected from hydrogen, deuterium, halogen and cyano ;
  • R 12 are each independently selected from halogen, C 1 -C 3 alkyl and C 3 -C 6 cycloalkylene, or adjacent R 12 together form a ring optionally substituted by one or more halogen or C 1 -C 3 alkyl substituted;
  • n is an integer from 1 to 3;
  • n is an integer from 1 to 3;
  • q is an integer of 0-6.
  • R 1 is selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 2 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R3 and R4 are each independently hydrogen or halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form a C3 - C6 cycloalkylene group optionally substituted with halogen ;
  • R 5 is C 1 -C 6 alkyl or C 1 -C 6 alkoxy
  • Heterocycle A is selected from the following structures:
  • Each R is independently selected from hydrogen, deuterium, halogen and cyano ;
  • n is an integer from 1 to 3;
  • n is an integer of 1-3.
  • R 1 is selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 -C 6 optionally substituted with halogen or deuterium alkoxy;
  • R 2 is each independently selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 optionally substituted with halogen or deuterium -C 6 alkoxy;
  • R3 and R4 are each independently selected from hydrogen, halogen, and C1 - C4 alkyl optionally substituted with halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form optionally substituted with halogen A C 3 -C 6 cycloalkylene group, or R 3 and R 4 on adjacent carbon atoms together form a C 3 -C 8 cycloalkane optionally substituted by halogen;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, C 3 -C 6 cycloalkyl optionally substituted by halogen or cyano, optionally substituted by halogen or cyano Heterocyclyl, C1 - C6alkoxy optionally substituted with halogen or cyano, and amino optionally substituted with alkyl;
  • R 6 is each independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, and C 1 -C 6 alkyl optionally substituted with halogen or deuterium;
  • R 7 is selected from the following groups:
  • R8 is selected from hydrogen, deuterium, halogen, cyano and C1 - C3 alkyl substituted with one or more halogens;
  • X is selected from oxygen atoms, -NH- and methylene optionally selected from halogen, C3 - C8 cycloalkyl, C3 - C6 cycloalkylene and C1 - C6 alkane is substituted with one or more substituents of the radical;
  • n is an integer from 1 to 3;
  • n is an integer of 1-4.
  • R 1 is selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 -C 6 optionally substituted with halogen or deuterium alkoxy;
  • R 2 is each independently selected from hydrogen, deuterium, halogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl optionally substituted with halogen or deuterium, and C 1 optionally substituted with halogen or deuterium -C 6 alkoxy;
  • R3 and R4 are each independently selected from hydrogen, halogen, and C1 - C4 alkyl optionally substituted with halogen, or R3 and R4 are taken together with the carbon atom to which they are commonly attached to form optionally substituted with halogen A C 3 -C 6 cycloalkylene group, or R 3 and R 4 on adjacent carbon atoms together form a C 3 -C 8 cycloalkane optionally substituted by halogen;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, C 3 -C 6 cycloalkyl optionally substituted by halogen or cyano, optionally substituted by halogen or cyano Heterocyclyl, C1 - C6alkoxy optionally substituted with halogen or cyano, and amino optionally substituted with alkyl;
  • R 6 is each independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, and C 1 -C 6 alkyl optionally substituted with halogen or deuterium;
  • R 7 is selected from the following groups:
  • R8 is selected from hydrogen, deuterium, halogen, cyano and C1 - C3 alkyl substituted with one or more halogens;
  • X is selected from oxygen atoms, -NH- and methylene optionally selected from halogen, C3 - C8 cycloalkyl, C3 - C6 cycloalkylene and C1 - C6 alkane is substituted with one or more substituents of the radical;
  • n is an integer from 1 to 3;
  • n is an integer of 1-4.
  • the present disclosure also provides a compound of formula (I-1), or a pharmaceutically acceptable salt thereof, or an isomer thereof,
  • R 1 is selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 2 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 5 is C 1 -C 3 alkyl or C 1 -C 3 alkoxy
  • R 6a and R 6b are each independently selected from hydrogen, deuterium, chlorine atom, fluorine atom and cyano group;
  • R8 is selected from hydrogen, deuterium, halogen, cyano, and C1 - C3 alkyl substituted with one or more halogens;
  • n is an integer of 1-3.
  • R 7 in the compound of formula (I-1) is the following optionally substituted with one or more substituents selected from methyl, fluorine, chlorine, halomethyl, and cyano group:
  • R8 is selected from hydrogen, deuterium, halogen and cyano.
  • the present disclosure also provides a compound of formula (I-1), or a pharmaceutically acceptable salt thereof, or an isomer thereof,
  • R 1 is selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 2 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 5 is C 1 -C 3 alkyl or C 1 -C 3 alkoxy
  • R 6a and R 6b are each independently selected from hydrogen, deuterium, chlorine atom, fluorine atom and cyano group;
  • R 7 and R 8 together with the atoms to which they are commonly attached form a 4-8 membered non-aromatic heterocyclic ring
  • the heterocyclic ring is monocyclic or bicyclic
  • the heterocycle is optionally selected from C 1 -C 3 alkylamide, halogen, oxo, C 1 -C 3 alkyl optionally substituted with halogen and C 1 -C 3 substituted with one or more substituents of the alkoxy group;
  • n is an integer of 1-3.
  • Heterocycle A is selected from the following structures:
  • R 6a and R 6b are each independently selected from hydrogen, deuterium, chlorine and fluorine atoms;
  • R 12 are each independently selected from halogen, C 1 -C 3 alkyl and C 3 -C 6 cycloalkylene, or adjacent R 12 together form a ring optionally substituted by one or more halogen or C 1 -C 3 alkyl substituted;
  • q is an integer of 0-6.
  • Heterocycle A is selected from the following structures:
  • R 6a and R 6b are each independently selected from hydrogen, deuterium, chlorine and fluorine atoms.
  • the present disclosure also provides a compound of formula (I-1), or a pharmaceutically acceptable salt thereof, or an isomer thereof,
  • R 1 is selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 2 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 5 is C 1 -C 3 alkyl or C 1 -C 3 alkoxy
  • R 6a and R 6b are each independently selected from hydrogen, deuterium, chlorine atom, fluorine atom and cyano group;
  • R7 is p is selected from 0, 1 and 2
  • R 9 and R 10 are each independently selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 3 -C 6 cyclohydrocarbyl, or R 9 and R 10 together with the nitrogen atom to which it is commonly attached forms a 4-6 membered heterocyclic group optionally substituted with one or more substituents selected from halogen, hydroxy and C 1 -C 3 alkyl;
  • R8 is selected from hydrogen, deuterium, halogen, cyano, and C1 - C3 alkyl substituted with one or more halogens;
  • n is an integer of 1-3.
  • R 7 in the compound of formula (I-1) is selected from the following groups:
  • R8 is selected from hydrogen, deuterium, halogen, cyano, and C1 - C3 alkyl substituted with one or more halogens.
  • the present disclosure also provides a compound of formula (I-1), or a pharmaceutically acceptable salt thereof, or an isomer thereof,
  • R 1 is selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 2 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkyl optionally substituted with halogen or deuterium, and halogen;
  • R 5 is C 1 -C 3 alkyl or C 1 -C 3 alkoxy
  • R 6a and R 6b are each independently selected from hydrogen, deuterium, chlorine atom, fluorine atom and cyano group;
  • R7 is p is selected from 0, 1 and 2
  • R 9 and R 10 are each independently selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 3 -C 6 cyclohydrocarbyl, or R 9 and R 10 together with the nitrogen atom to which it is commonly attached forms a 4-6 membered heterocyclic group optionally substituted with one or more substituents selected from halogen, hydroxy and C 1 -C 3 alkyl
  • R ' is selected from hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cyclohydrocarbyl, aryl and heteroaryl;
  • R8 is selected from hydrogen, deuterium, halogen, cyano, and C1 - C3 alkyl substituted with one or more halogens;
  • n is an integer of 1-3.
  • R 7 in the compound of formula (I-1) is selected from the following groups:
  • R8 is selected from hydrogen, deuterium, halogen, cyano, and C1 - C3 alkyl substituted with one or more halogens.
  • the present disclosure also provides a compound shown below, or a pharmaceutically acceptable salt thereof, or an isomer thereof,
  • the present disclosure provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof, comprising the steps of:
  • the compound represented by the formula (Ia) is reacted with the compound represented by the formula (Ib) under basic conditions to obtain the compound represented by the formula (Ic); the compound represented by the formula (Ic) is subjected to a reduction reaction to obtain the compound represented by the formula (Id); The compound represented by the formula (Id) and the compound represented by the formula (Ie) are subjected to ring-closure reaction under acidic conditions to obtain the compound represented by the formula (I);
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, m and n are as defined for compounds of formula (I); and Y is selected from halogen, sulfonyl and sulfinyl.
  • the present disclosure also provides another method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof, comprising the steps of:
  • the compound represented by the formula (Ia) is reacted with the compound represented by the formula (Ib) under basic conditions to obtain the compound represented by the formula (Ic); the compound represented by the formula (Ic) is subjected to a reduction reaction to obtain the compound represented by the formula (Id);
  • the compound represented by the formula (Id) and the compound represented by the formula (If) are subjected to ring-closure reaction under acidic conditions to obtain the compound represented by the formula (Ig); the compound represented by the formula (Ig) is reacted under the action of a catalyst to obtain the compound represented by the formula (I).
  • the catalyst is selected from palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium, 1,1'-bis(dibenzylphosphorus)dipentyl iron palladium dichloro, tris(dibenzylideneacetone)dipalladium, 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl , [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), cuprous iodide, cuprous bromide, cuprous chloride and copper triflate ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, m and n are as defined in the compound of formula I;
  • Y and Z are each independently selected from halogen, sulfonyl and sulfinyl.
  • the present disclosure also provides methods for preparing the compounds or pharmaceutically acceptable salts thereof, or isomers thereof. In particular, it is prepared by the method of the examples.
  • the present disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described in the present disclosure, or a pharmaceutically acceptable salt thereof, or an isomer thereof.
  • the composition will also comprise at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the unit dose of the compound or a pharmaceutically acceptable salt thereof, or an isomer thereof is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains from 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.
  • the present disclosure also relates to the use of the compound or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of a disease associated with P2X3 activity.
  • the present disclosure also relates to the compound or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure also relates to the compound or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a pharmaceutical composition comprising the same, for use in the treatment of diseases associated with P2X3 activity.
  • the present disclosure also relates to a method of treating a disease associated with P2X3 activity, comprising administering to a patient in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a pharmaceutical composition comprising the same .
  • the P2X3 activity-related disease refers to a P2X3 overactivity-related disease.
  • the compounds of the present disclosure are highly selective for P2X3 and can avoid taste loss.
  • compounds of the present disclosure are more than 20-fold more potent at P2X3 homologous receptor antagonism than at P2X2/3 heteromeric receptors.
  • the compounds of the present disclosure are more than 30-fold more potent at P2X3 homologous receptor antagonism than at P2X2/3 heteromeric receptors.
  • the compounds of the present disclosure are more than 50-fold more potent at P2X3 homologous receptor antagonism than at P2X2/3 heteromeric receptors.
  • the compounds of the present disclosure are more than 100-fold more potent at P2X3 homologous receptor antagonism than at P2X2/3 heteromeric receptors.
  • the present disclosure also relates to the use of the compound or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for treating pain, urinary tract disease, cough and other diseases.
  • the present disclosure also relates to the compound or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a pharmaceutical composition comprising the same, for use in the treatment of pain, urinary tract disease, cough and other diseases.
  • the present disclosure also relates to a method for treating pain, urinary tract disease, cough and other diseases, comprising administering to a patient in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a compound comprising the same. pharmaceutical composition.
  • the pain can be, for example, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, pain caused by rheumatoid arthritis, migraine, and visceral pain.
  • Urinary tract disorders such as overactive bladder (also known as urinary incontinence), pelvic hypersensitivity, and urethritis.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a pharmaceutical composition comprising the same may be used to treat gastrointestinal disorders, including, for example, constipation and functional gastrointestinal disorders (eg, bowel disease) Inflammatory syndrome or functional dyspepsia); can be used in the treatment of cancer; can be used in the treatment of cardiovascular disorders or in cardioprotection after myocardial infarction; can be used as an immunomodulatory agent, especially in the treatment of autoimmune diseases (such as arthritis), for skin transplantation, organ transplantation, or similar surgical needs, for collagen disease, for allergy, or as an antineoplastic or antiviral agent; may be used to treat multiple sclerosis, Parkinson's Parkinson's disease and Huntington's chorea; may be used to treat depression, anxiety, stress-related disorders (eg, post-traumatic stress disorder, panic disorder, social phobia, or obsessive-compulsive disorder), premature ejaculation, Psychosis, traumatic brain injury
  • gastrointestinal disorders
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or an isomer thereof may be formulated for oral, buccal, vaginal, rectal, via inhalation, via insufflation, intranasal, sublingual, topical, or parenteral (eg, intramuscular) , subcutaneous, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, intracerebroventricular or by injection into the joint) dosage form.
  • parenteral eg, intramuscular
  • the pharmaceutically acceptable salts of the compounds described in this disclosure can be selected from inorganic or organic salts.
  • treatment refers to the administration of a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • Prophylactic disease refers to subjects who have not yet developed a disease under prophylactic treatment, but are susceptible to, or at risk for, a particular disease.
  • Reference to “treating a disease” refers to treating a patient already suffering from a disease to ameliorate or stabilize the patient's condition.
  • any isotopically labeled (or "radiolabeled") derivative of a compound described in this disclosure, or a pharmaceutically acceptable salt thereof, or an isomer thereof, is covered by this disclosure.
  • Such derivatives are those in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature.
  • radionuclides examples include 2 H (also written as “D” for deuterium), 3 H (also written as “T” for tritium), 11C , 13C , 14C , 13N , 15N , 15O , 17O , 18O , 18F , 36Cl , 82Br , 75Br , 76Br , 77Br , 123I , 124I , 125I , 31P , 32P , 35S , and 131 I.
  • the radionuclide used will depend on the specific application of the radiolabeled derivative. For example, for in vitro receptor labeling and competition assays, 3H or14C are often useful.
  • the radionuclide is3H . In some embodiments, the radionuclide is14C . In some embodiments, the radionuclide is11C . And in some embodiments, the radionuclide is18F .
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) of deuterium (ie, at least 45 % of deuterium incorporated).
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock animals agents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • an “effective amount” or “therapeutically effective amount” as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
  • the bond no configuration is specified, i.e. the bond The configuration can be E or Z, or both E and Z configurations.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton transfer such as keto-enol and imine-enamine, lactam-lactam isomerizations .
  • An example of a lactam-lactam equilibrium is between A and B as shown below.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Alkyl refers to straight or branched chain alkyl groups, including straight and branched chain groups of 1 to 20 carbon atoms. Preferably it contains 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, eg methyl, ethyl, n-propyl, isopropyl and the like.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo , amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, 6 to 10 aryl or 5 to 10 heteroaryl, the An alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted by one or more halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy replace.
  • Alkoxy refers to an alkyloxy group, wherein alkyl is as defined above, eg, methoxy, ethoxy, and the like. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino , C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl Substituted with one or more selected from halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy.
  • Heterocyclyl refers to a non-aromatic ring group containing 1 to 6 heteroatoms, 3 to 18 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Heterocyclyl preferably contains 1 to 4 heteroatoms, more preferably 1 to 3 heteroatoms, even more preferably 1 or 2 heteroatoms; Heterocyclyl preferably has 3 to 12 members, more preferably 3 to 8 yuan or 4 to 8 yuan, even more preferably 4 to 6 yuan, even more preferably 5 yuan or 6 yuan.
  • a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a spiro or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocyclyl group may optionally be The nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated.
  • other moieties optionally contain heteroatoms.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • Heteroaryl refers to an aromatic ring group containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 4 to 6 membered or 6 to 12 membered, more preferably 5 membered or 6 membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, etc.
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • Aryl or heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano group, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or hetero Cycloalkyl is substituted with one or more selected from halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy.
  • Cyclohydrocarbyl or “cycloalkyl” refers to a stable, non-aromatic monocyclic or polycyclic alkyl group consisting only of carbon atoms and hydrogen atoms, which may contain spiro or bridged ring systems, having 3 to 15 carbon atoms , 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms, and it is saturated or unsaturated, and is attached to the rest of the molecule by a single bond.
  • Monocyclic cyclic hydrocarbon groups include non-bridged cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl are or more selected from halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy substituted.
  • Cycloalkylene or “cycloalkylene” refers to a divalent cyclic hydrocarbon group derived from a cyclic hydrocarbon group. E.g, Wait. Can be substituted or unsubstituted, when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is replaced by one or more Substituted from halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • amino refers to -NH2 .
  • nitro refers to -NO2 .
  • Substituted means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in a group are independently of each other substituted by the corresponding number of substituents.
  • “Pharmaceutically acceptable salts” refer to salts of compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity.
  • the salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia.
  • Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC uses Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7 ⁇ m 2.1*50mm column, Ultimate XB-C18 3.0 *150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).
  • MS was measured with a Waters SQD2 mass spectrometer, scanned in positive/negative ion mode, with a mass scan range of 100-1200.
  • Chiral HPLC analysis was determined using Chiralpak IC-3 100 ⁇ 4.6mm ID, 3 ⁇ m, Chiralpak AD-3 150 ⁇ 4.6mm ID, 3 ⁇ m, Chiralpak AD-3 50 ⁇ 4.6mm ID, 3 ⁇ m, Chiralpak AS-3 150 ⁇ 4.6mm ID, 3 ⁇ m, Chiralpak AS-3 100 ⁇ 4.6mm ID, 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm ID, 3 ⁇ m, ChiralCel OD-3 100 ⁇ 4.6mm ID, 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm ID, 5 ⁇ m, ChiralCel OJ-3 150 ⁇ 4.6mm ID, 3 ⁇ m column.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • the chiral preparative column used DAICEL CHIRALPAK IC (250mm*30mm, 10 ⁇ m) or Phenomenex-Amylose-1 (250mm*30mm, 5 ⁇ m).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying the compound, and the volume of the solvent
  • TLC thin layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • the preparation of the positive compound MK-7264 refers to the experimental procedure of the patent WO2005095359.
  • Step 1 tert-butyl (2S)-2-[(1,3-dicarbonyl-2,3-dihydro-1H-isoindol-2-yl)methyl]morpholine-4-carboxylate ( 1a)
  • Step 6 1-[4-(1- ⁇ [(2R)-4-acetylmorpholin-2-yl]methyl ⁇ -5-methyl-1H-1,3-benzodiazole-2- yl)-3,5-difluorophenyl]pyrrolidin-2-one (1)
  • Example 1 for the synthetic procedure of Example 2.
  • step 1 tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate is used to replace (2R)-2-(hydroxymethyl)morpholine-4-carboxylate tert-butyl ester
  • step 6 tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate is replaced by chlorine Methyl formate replaces acetic anhydride.
  • step 5 4-bromo-2-chlorobenzaldehyde is used to replace 4-bromo-2,6-difluorobenzaldehyde.
  • step 3 4-(difluoromethyl)-1-fluoro-2-nitrobenzene is used instead of 1-fluoro-4-methyl-2-nitrobenzene.
  • step 1 of Example 1 For the synthesis steps of compound 6b, see step 1 of Example 1. Wherein, compound 6a was used instead of (2R)-2-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester.
  • Step 6 Methyl(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methyl-3H-imidazo[4,5- b]Pyridin-3-yl)methyl)morpholine-4-carboxylate (6)
  • step 5 of Example 1 Compound 1d was replaced by compound 6e, and 4-bromo-2,6-difluorobenzaldehyde was replaced by 3,5-difluoro-4-formyl-N-methylbenzamide.
  • Step 4 Methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-imidazo[4,5- b]Pyridin-1-yl)methyl)morpholine-4-carboxylate (7)
  • step 5 of Example 1 Compound 1d was replaced by compound 7c, and 4-bromo-2,6-difluorobenzaldehyde was replaced by 3,5-difluoro-4-formyl-N-methylbenzamide.
  • Step 3 Methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methyl-3H-imidazo[4,5- c]Pyridin-3-yl)methyl)morpholine-4-carboxylate (8)
  • step 5 of Example 1 For the synthesis steps of compound 8, see step 5 of Example 1. Wherein, compound 1d was replaced by compound 8b, and 4-bromo-2,6-difluorobenzaldehyde was replaced by 3,5-difluoro-4-formyl-N-methylbenzamide.
  • Step 5 Methyl (S)-2-((2-(2,6-difluoro-4-(2-carbonylpyrrolidin-1-yl)phenyl)-7-methylimidazo[1,2 -a]Pyridin-3-yl)methyl)morpholine-4-carboxylate (9)
  • Step 4 (S)-1-(2-(((2-amino-4-chlorophenyl)amino)methyl)morpholino)ethane-1-one (10d)
  • Step 5 (S)-1-(2-((2-(4-Bromo-2,6-difluorophenyl)-5-chloro-1H-benzo[d]imidazol-1-yl)methyl )morpholino)ethan-1-one (10e)
  • Step 1 (S)-1-(2-(((5-Fluoro-4-methyl-2-nitrophenyl)amino)methyl)morpholino)ethane-1-one (11a)
  • Step 2 (S)-1-(2-((2-(4-Bromo-2-chloro-6-fluorophenyl)-6-fluoro-5-methyl-1H-benzo[d]imidazole- 1-yl)methyl)morpholino)ethan-1-one (11b)
  • Step 3 (S)-1-(4-(1-((4-Acetylmorpholin-2-yl)methyl)-6-fluoro-5-methyl-1H-benzo[d]imidazole- 2-yl)-3-chloro-5-fluorophenyl)pyrrolidin-2-one (11)
  • Step 1 tert-butyl (S)-2-(((4-chloro-5-fluoro-2-nitrophenyl)amino)methyl)morpholine-4-carboxylate (12a)
  • step 3 of Example 10 For the synthesis steps of compound 12a, see step 3 of Example 10. Wherein, 1-fluoro-4-chloro-2-nitrobenzene was replaced by 1-chloro-2,4-difluoro-5-nitrobenzene.
  • Step 2 tert-butyl (S)-2-(((2-amino-4-chloro-5-fluorophenyl)amino)methyl)morpholine-4-carboxylate (12b)
  • step 5 of Example 10 For the synthesis steps of compound 12c, see step 5 of Example 10.
  • the compound 10d was replaced by compound 12b, and the 4-bromo-2,6-difluorobenzaldehyde was replaced by 4-bromo-2-chloro-6-fluorobenzaldehyde.
  • Step 4 (S)-1-(2-((2-(4-Bromo-2-chloro-6-fluorophenyl)-5-chloro-6-fluoro-1H-benzo[d]imidazole-1 -yl)methyl)morpholino)ethan-1-one (12d)
  • Step 5 (S)-1-(4-(1-((4-acetylmorpholin-2-yl)methyl)-5-chloro-6-fluoro-1H-benzo[d]imidazole-2 -yl)-3-chloro-5-fluorophenyl)pyrrolidin-2-one (12)
  • Step 1 (S)-1-(2-(((4-Chloro-2-fluoro-6-nitrophenyl)amino)methyl)morpholino)ethane-1-one (13a)
  • step 3 of Example 10 For the synthesis steps of compound 13a, see step 3 of Example 10. Wherein, 5-chloro-1,2-difluoro-3-nitrobenzene was used instead of 1-fluoro-4-chloro-2-nitrobenzene.
  • Step 2 (S)-1-(2-(((2-amino-4-chloro-6-fluorophenyl)amino)methyl)morpholino)ethane-1-one (13b)
  • Step 3 (S)-1-(2-((2-(4-Bromo-2,6-difluorophenyl)-5-chloro-7-fluoro-1H-benzo[d]imidazole-1- yl)methyl)morpholino)ethan-1-one (13c)
  • Step 4 (S)-1-(4-(1-((4-acetylmorpholin-2-yl)methyl)-5-chloro-7-fluoro-1H-benzo[d]imidazole-2 -yl)-3,5-difluorophenyl)pyrrolidin-2-one (13)
  • Step 1 tert-butyl (S)-2-(((4-bromo-2-nitrophenyl)amino)methyl)morpholine-4-carboxylate (14a)
  • Step 2 tert-butyl (S)-2-(((4-(methyl-d 3 )-2-nitrophenyl)amino)methyl)morpholine-4-carboxylate (14b)
  • Step four (S)-1-(4-(1-((4-acetylmorpholin-2-yl)methyl)-5-(methyl-d3)-1H-benzo[d]imidazole- 2-yl)-3,5-difluorophenyl)pyrrolidin-2-one (14)
  • Step 1 tert-butyl (S)-2-((2-(4-bromo-2-chloro-6-fluorophenyl)-5-methyl-1H-benzo[d]imidazol-1-yl) Methyl)morpholine-4-carboxylate (15a)
  • step 5 of Example 1 For the synthesis steps of compound 15a, see step 5 of Example 1.
  • the 4-bromo-2,6-difluorobenzaldehyde was replaced by 4-bromo-2-chloro-6-fluorobenzaldehyde.
  • Step 2 (R)-1-(3-Chloro-5-fluoro-4-(5-methyl-1-(morpholin-2-ylmethyl)-1H-benzo[d]imidazole-2- yl)phenyl)pyrrolidin-2-one (15b)
  • Step 3 (S)-1-(3-Chloro-4-(1-((4-(cyclopropylcarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d ]imidazol-2-yl)-5-fluorophenyl)pyrrolidin-2-one (15)
  • Step 5 tert-butyl (S)-2-((2-(6-chloro-8-fluoro-3-carbonyl-3,4-dihydro-2H-benzo[b][1,4]oxazine -7-yl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate (17e)
  • step 3 of Example 14 For the synthesis steps of compound 17e, see step 3 of Example 14. Wherein, compound 1c was used to replace compound 14b, and compound 17d was used to replace 4-bromo-2,6-difluorobenzaldehyde.
  • Step 6 (S)-6-Chloro-8-fluoro-7-(5-methyl-1-((4-propionylmorpholin-2-yl)methyl)-1H-benzo[d]imidazole -2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (17)
  • Test Example 1 Evaluation of Biological Activity in Vitro
  • Digest 1321N1 cells stably transfected with hP2X3 and hP2X2/3 receptors, resuspend and count in plating medium (DMEM+10% DFBS) after centrifugation, and adjust cells to 2*10 5 cells/mL , spread 50 ⁇ L of cells in each well of a 384-well assay plate, and place them in a 5% CO 2 , 37° C. incubator for 16-24 hours.
  • plating medium DMEM+10% DFBS
  • Test compounds at 180 times the desired concentration (20 mM DMSO stock solution) were prepared in DMSO, and 500 nL per well was added to a 384-well compound plate, supplemented with 30 ⁇ L FLIPR buffer (1*HBSS + 2 mM CaCl containing 1.26 mM Ca 2+ ). 2 + 20 mM HEPES), shake for 20-40 min to mix.
  • the difference between the signal peak and the trough was taken as the basic data, the highest concentration of the positive drug was taken as the 100% inhibition rate, and the DMSO data was taken as the 0% inhibition rate, the inhibitory effect curve of the compound was fitted on the software Graphpad Prism 6 and the IC 50 was calculated value.
  • 150-donor pooled human liver microsomes purchased from Corning, Cat. No. 452117) were used to assess representative substrate metabolic responses of the five major human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5). Determination of different concentrations of test compounds for phenacetin (CYP1A2), diclofenac sodium (CYP2C9), S-mephentoin (CYP2C19), bufurolol hydrochloride by liquid chromatography tandem mass spectrometry (LC/MS/MS) Effects of salt (CYP2D6) and midazolam (CYP3A4/5) on metabolic responses.
  • test compound concentration of 0.1, 0.3, 1, 3, 10, 30 ⁇ mol/L or positive compound or blank control and mixed human liver microsomes (0.2mg/mL) in a reaction system of 200 ⁇ L (100mmol/L phosphate buffer, pH 7.4, containing 0.3% by volume respectively) DMSO, 0.6% acetonitrile, 0.1% methanol) were incubated at 37°C for 5 minutes.
  • Peak area ratio metabolite peak area/internal standard peak area
  • Residual activity ratio (%) peak area ratio of the test compound group / peak area ratio of the blank group
  • CYP median inhibitory concentration (IC 50 ) was calculated by Excel XLfit 5.3.1.3.
  • IC50 CYP median inhibitory concentration
  • the compound concentration in the reaction system was determined by LC/MS/MS to calculate the intrinsic clearance rate of the test compound and to evaluate the in vitro metabolic stability in human hepatocytes.
  • the reaction was initiated by adding 247.5 ⁇ L of 1 ⁇ 10 6 cells/mL mixture of human hepatocytes (purchased from Bioreclamation IVT, Cat. No. S01205) and 2.5 ⁇ L of 100 ⁇ M test compound or positive control to the incubation plate. Incubation was performed at 37°C and 600 rpm. Transfer 20 ⁇ L of the incubation system to the stop plate at 0.5, 5, 15, 30, 45, 60, 80, 100 and 120 minutes, respectively. It was then vortexed for 2 minutes. The stop plate was centrifuged at 4000 rpm for 20 minutes. Transfer 40 ⁇ L of the supernatant of each compound to a 96-well injection plate, and then add 160 ⁇ L of purified water to dilute the samples.
  • the resulting samples were quantified by ion chromatograms. Residual ratios were calculated based on the peak area of the test compound or positive control. The slope k was determined by linear regression of the natural log value of the residual rate against incubation time using Microsoft Excel.
  • Intrinsic clearance (in vitro CL int , ⁇ L/min/ 10 cells) was calculated from the slope values according to the following equation:
  • V incubation volume (0.25 mL);
  • N number of cells per well (0.25 x 10 6 cells)
  • the apparent permeability coefficient (P app ) of the analyzed drugs was determined by liquid chromatography tandem mass spectrometry (LC/MS/MS) by the Caco-2 cell model.
  • HBSS 25 mM HEPES, pH 7.4
  • Caco-2 cells purchased from ATCC
  • the rate of drug transport from basal to apical was determined. Add 308 ⁇ L of HBSS (25 mM HEPES, pH 7.4) containing 10 ⁇ M of the test compound to the well of the plate at the basolateral end, and immediately remove 8 ⁇ L of sample to a solution containing 72 ⁇ L of HBSS (25 mM HEPES, pH 7.4) and 240 ⁇ L of acetonitrile (containing 100 nM Alprazolam, caffeine 200 nM and 100 nM tolbutamide) in a new 96-well plate as initial dosing end sample (BA), vortexed at 1000 rpm for 10 min, topped with 100 ⁇ L HBSS (25 mM) HEPES, pH 7.4).
  • HBSS 25 mM HEPES, pH 7.4
  • acetonitrile containing 100 nM Alprazolam, caffeine 200 nM and 100 nM tolbutamide
  • the samples were centrifuged at 4000 rpm for 30 minutes. Transfer 100 ⁇ L of the supernatant to a new 96-well plate. All samples were added with 100 ⁇ L of pure water and analyzed by LC-MS/MS.
  • Papp is the apparent permeability (cm/s ⁇ 10 -6 );
  • dQ/dt is the drug delivery rate (pmol/s);
  • A is the surface area of the membrane (cm 2 );
  • D 0 is the initial feed-side drug concentration (nM; pmol/cm 3 ).
  • the outflow ratio can be determined by the following formula:
  • Papp(B-A) is the apparent permeability coefficient from the basal end to the apical direction
  • Papp(A-B) is the apparent permeability coefficient from the apical to the basal direction.
  • Rats were used as test animals, and the drug concentration in plasma at different time points was determined by LC/MS/MS method after intragastric administration of the compounds of the present disclosure in rats.
  • the pharmacokinetic behavior of the disclosed compounds in rats was studied, and their pharmacokinetic characteristics were evaluated.
  • Oral administration Weigh a certain amount of medicine, add 0.5% hypromellose, 0.1% Tween 80 and 99.4% volume water to prepare a 1 mg/mL white suspension.
  • Rats were administered the compounds of the present disclosure by gavage, and 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in a test tube containing EDTA-K2 at 4°C, 4000 rpm/ Plasma was separated by centrifugation for 5 minutes and stored at -75°C.
  • Determination of the content of the test compound in rat plasma after intragastric administration of drugs with different concentrations take 50 ⁇ L of rat plasma at each time after administration, add 200 ⁇ L of acetonitrile solution of internal standard dexamethasone (50 ng/mL), vortex Mixed for 30 seconds, centrifuged at 4°C, 4700 rpm for 15 minutes, the supernatant of the plasma sample was diluted three times with water, and 2.0 ⁇ L was taken for LC/MS/MS analysis.
  • rat pharmacokinetic parameters of some compounds of the present disclosure are as follows:

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Abstract

一种苯并咪唑类衍生物、其制备方法及医药用途。具体而言，一种通式(I)所示的苯并咪唑类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是用于治疗与P2X3活性相关的疾病的用途。

Description

苯并咪唑类衍生物、其制备方法及医药用途 技术领域
本公开涉及医药领域，具体涉及一类新的苯并咪唑类衍生物，其制备方法，以及在医药上的应用。
背景技术
P2X受体是阳离子可渗透的配体门控离子通道家族，其响应于细胞外腺苷5'-三磷酸(ATP)的结合而打开。它们属于更大的受体家族，称为嘌呤能受体。P2X受体存在于多种生物中，包括人、小鼠、大鼠、兔、鸡、斑马鱼、牛蛙、吸虫和变形虫。已经鉴定了编码P2X亚基的七个独立基因，并将其命名为P2X1至P2X7。不同的亚基对嘌呤能激动剂和拮抗剂表现出不同的敏感性。
P2X3受体在单一亚基上存在4个ATP结合位点，由2个跨膜结构域、位于胞内的N-末端和C-末端、位于胞外环结构的保守序列构成。在特异性的与伤害信息有关的中小直径神经元中均发现有P2X3受体的高度表达。同时，P2X3受体也参与一些非伤害性感觉的传递。它已被证实，P2X3受体参与膀胱感觉功能，是一个关键的受体介导的膀胱感觉信号，在含有丰富的感觉神经纤维的膀胱黏膜组织中的表达。在咽黏膜的感觉神经纤维中也有P2X3的表达，它与味觉的传导、形成有关。
当机体受到伤害或神经损伤后释放大量ATP，激活突触前膜P2X3受体，引起大量Ca2 +内流，细胞内钙浓度增加激活蛋白激酶A(protein kinase A，PKA)、蛋白激酶C(protein kinase C，PKC)，使得PKA、PKC磷酸化，同时促进了谷氨酸释放，进一步激活NMDA受体，导致兴奋性突触后电流的产生，引起中枢敏感化。许多研究表明，P2X3受体表达上调可导致痛敏形成，参与疼痛的信号传递。
MK-7264是一个P2X3受体活性拮抗剂，其对人同源重组hP2X3和hP2X2/3的IC 50值分别是～30nM和100-250nM，目前其用于慢性咳嗽患者治疗的用途已经进行到临床III期。
发明内容
本公开提供如式(I)化合物、或其可药用盐、或其异构体，
Figure PCTCN2021112386-appb-000001
其中，R 1选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 2各自独立地选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 3和R 4各自独立地选自氢、卤素和任选地被卤素取代的C 1-C 4烷基，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
R 6各自独立地选自氢、氘、卤素、氰基、环丙基和任选地被卤素或氘取代的C 1-C 6烷基；
R 7和R 8各自独立地选自：
a)氢、氘、卤素、氰基、氨基、羟基、任选地被卤素取代的C 1-C 6烷基、砜、亚砜、磺酰胺、亚磺酰胺、C 1-3的羧基和任选地被卤素取代的C 1-C 6烷氧基；
b)
Figure PCTCN2021112386-appb-000002
p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 6烷基、C 1-C 6烷氧基以及C 3-C 8环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被选自卤素、羟基、氰基、C 1-C 6卤代烷基和C 1-C 6烷基的一个或多个取代基取代；R’选自氢、C 1-C 6烷基、C 3-C 8环烃基、芳基和杂芳基；并且在
Figure PCTCN2021112386-appb-000003
中，当p为0时，R 9和R 10的组合不为氢和甲基；
c)
Figure PCTCN2021112386-appb-000004
d)杂环基和杂芳基，所述的杂环基和杂芳基各自任选地被选自氧代、卤素、 羟基、羰基、C 1-C 6烷基和氰基的一个或多个取代基取代，所述的C 1-C 6烷基任选地被一个或多个卤素取代；和
e)
Figure PCTCN2021112386-appb-000005
其中，R 11选自C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、C 3-C 8环烃基、杂环基、C 1-C 6氰代烷基、C 3-C 8环烃基氧基和任选被C 1-C 6烷基取代的氨基；或者
R 7和R 8与其共同连接的原子一起形成任选被取代的芳香或非芳香杂环；
X选自氧原子、-NH-和亚甲基，所述亚甲基任选地被选自卤素、C 3-C 8环烃基、C 3-C 6亚环烃基和C 1-C 6烷基的一个或多个取代基取代；
m为1-3的整数；且
n为1-4的整数。
在一些实施方案中，R 7和R 8各自独立地选自：
a)氢、氘、卤素、氰基、氨基、砜、磺酰胺、亚磺酰胺和被一个或多个卤素取代的C 1-C 3烷基；
b)
Figure PCTCN2021112386-appb-000006
p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 3烷基、C 1-C 3烷氧基和C 3-C 6环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被选自卤素、羟基和C 1-C 3烷基的一个或多个取代基取代；R’选自氢、C 1-C 3烷基、C 3-C 6环烃基、芳基和杂芳基；并且在
Figure PCTCN2021112386-appb-000007
中，当p为0时，R 9和R 10的组合不为氢和甲基；
c)
Figure PCTCN2021112386-appb-000008
d)4-6元杂环基或杂芳基，所述的杂环基或杂芳基任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基取代，所述的C 1-C 3烷基可以任选地被一个或多个卤素取代；和
e)
Figure PCTCN2021112386-appb-000009
其中，R 11选自C 1-C 3烷基、C 1-C 3烷氧基、5-6元芳基或杂芳基、3-8元环烃基、3-8元杂环基、C 1-C 3氰代烷基、C 3-C 6环烃基氧基和任选被C 1-C 3烷基取代的氨基。
在一些实施方案中，R 7为4-6元杂环基或杂芳基，所述的杂环基或杂芳基任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基取代， 所述的C 1-C 3烷基任选地被一个或多个卤素取代；且
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基。
在一些实施方案中，R 7为4-6元杂环基，所述杂环基包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环基任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基取代，所述的C 1-C 3烷基任选地被一个或多个卤素取代；且
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基。
在一些实施方案中，R 7为5元杂环基，所述杂环基包含-NH-C(＝O)-，所述杂环基任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基取代，所述的C 1-C 3烷基任选地被一个或多个卤素取代；且
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基。
在一些实施方案中，式(I)化合物中，
R 1选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 2各自独立地选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 3和R 4各自独立地选自氢、卤素和任选地被卤素取代的C 1-C 4烷基，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
R 6各自独立地选自氢、氘、卤素、氰基、环丙基和任选地被卤素或氘取代的C 1-C 6烷基；
R 7和R 8与其共同连接的原子一起形成3-12元芳香或非芳香杂环，所述杂环为单环或双环，所述杂环任选被选自C 1-C 6烷基酰胺、卤素、氧代、任选地被卤素取代的C 1-C 6烷基和C 1-C 6烷氧基的一个或多个取代基取代；
X选自氧原子、-NH-和亚甲基，所述亚甲基任选地被选自卤素、C 3-C 8环烃基、C 3-C 6亚环烃基和C 1-C 6烷基的一个或多个取代基取代；
m为1-3的整数；且
n为1-4的整数。
在一些实施方案中，R 7和R 8与其共同连接的原子一起形成3-12元非芳香杂环，所述杂环为单环或双环，所述杂环包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环任选被选自C 1-C 6烷基酰胺、卤素、氧代、任选地被卤素取代的C 1-C 6烷基和C 1-C 6烷氧基的一个或多个取代基取代。
在一些实施方案中，R 7和R 8与其共同连接的原子一起形成4-8元非芳香杂环，所述杂环为单环或双环，所述杂环包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环任 选被选自C 1-C 3烷基酰胺、卤素、氧代、任选地被卤素取代的C 1-C 3烷基和C 1-C 3烷氧基的一个或多个取代基取代。
在一些实施方案中，式(I)化合物中，
R 1选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 2各自独立地选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 3和R 4各自独立地选自氢、卤素和任选地被卤素取代的C 1-C 4烷基，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
R 6各自独立地选自氢、氘、卤素、氰基、环丙基和任选地被卤素或氘取代的C 1-C 6烷基；
R 7为
Figure PCTCN2021112386-appb-000010
p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 3烷基、C 1-C 3烷氧基和C 3-C 6环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被选自卤素、羟基和C 1-C 3烷基的一个或多个取代基取代；
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基；
X选自氧原子、-NH-和亚甲基，所述亚甲基任选地被选自卤素、C 3-C 8环烃基、C 3-C 6亚环烃基和C 1-C 6烷基的一个或多个取代基取代；
m为1-3的整数；且
n为1-4的整数。
在一些实施方案中，式(I)化合物中，
R 7为
Figure PCTCN2021112386-appb-000011
p为0或1，R 9选自氢、C 1-C 3烷基、C 1-C 3烷氧基和C 3-C 6环烃基，R 10为氢，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被一个或多个卤素取代；且
R 8选自氢、氘和卤素。
在一些实施方案中，式(I)化合物中，
R 1选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 2各自独立地选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 3和R 4各自独立地选自氢、卤素和任选地被卤素取代的C 1-C 4烷基，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
R 6各自独立地选自氢、氘、卤素、氰基、环丙基和任选地被卤素或氘取代的C 1-C 6烷基；
R 7为
Figure PCTCN2021112386-appb-000012
p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 3烷基、C 1-C 3烷氧基和C 3-C 6环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被选自卤素、羟基和C 1-C 3烷基的一个或多个取代基取代；R’选自氢、C 1-C 3烷基、C 3-C 6环烃基、芳基和杂芳基；
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基；
X选自氧原子、-NH-和亚甲基，所述亚甲基任选地被选自卤素、C 3-C 8环烃基、C 3-C 6亚环烃基和C 1-C 6烷基的一个或多个取代基取代；
m为1-3的整数；且
n为1-4的整数。
在一些实施方案中，式(I)化合物中，
R 7为
Figure PCTCN2021112386-appb-000013
p为0或1，R 9选自氢、C 1-C 3烷基、C 1-C 3烷氧基和C 3-C 6环烃基，R 10为氢，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被一个或多个卤素取代；R’选自氢、C 1-C 3烷基、C 3-C 6环烃基、芳基和杂芳基；且
R 8选自氢、氘和卤素。
在一些实施方案中，式(I)化合物中，
R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 6烷基和卤素；
R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 6烷基和卤素；
R 3和R 4各自独立地为氢或卤素，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的 C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
R 6各自独立地选自氢、氘、卤素、氰基、环丙基和任选地被卤素或氘取代的C 1-C 6烷基；
R 7和R 8各自独立地选自：
a)氢、氘、卤素、氰基、氨基、羟基、任选地被卤素取代的C 1-C 6烷基、砜、亚砜、磺酰胺、亚磺酰胺、C 1-3的羧基和任选地被卤素取代的C 1-C 6烷氧基；
b)
Figure PCTCN2021112386-appb-000014
p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 3烷基、C 1-C 3烷氧基和C 3-C 6环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被选自卤素、羟基和C 1-C 3烷基的一个或多个取代基取代；R’选自氢、C 1-C 3烷基、C 3-C 6环烃基、芳基和杂芳基；并且在
Figure PCTCN2021112386-appb-000015
中，当p为0时，R 9和R 10的组合不为氢和甲基；
c)
Figure PCTCN2021112386-appb-000016
d)杂环基和杂芳基，所述的杂环基和杂芳基各自任选地被选自氧代、卤素、羟基、羰基、C 1-C 6烷基和氰基的一个或多个取代基取代，所述的C 1-C 6烷基任选地被一个或多个卤素取代；和
e)
Figure PCTCN2021112386-appb-000017
其中，R 11选自C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、C 3-C 8环烃基、杂环基、C 1-C 6氰代烷基、C 3-C 8环烃基氧基和任选被C 1-C 6烷基取代的氨基；或者
R 7和R 8与其共同连接的原子一起形成任选被取代的芳香或非芳香杂环；
X选自氧原子、-NH-和亚甲基，所述亚甲基任选地被选自卤素、C 3-C 8环烃基、C 3-C 6亚环烃基和C 1-C 6烷基的一个或多个取代基取代；
m为1-3的整数；且
n为1-4的整数。
在一些实施方案中，R 5为任选地被卤素或氰基取代的C 1-C 6烷基或任选地被卤素或氰基取代的C 1-C 6烷氧基；
R 6各自独立地选自氢、氘、卤素和氰基；且
n为1-4的整数。
在一些实施方案中，R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 3和R 4各自独立地为氢或卤素，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基；
R 5为C 1-C 6烷基或C 1-C 6烷氧基；
R 6各自独立地选自氢、氘、卤素和氰基；
R 7和R 8各自独立地选自：
a)氢、氘、卤素、氰基、氨基、羟基、任选地被卤素取代的C 1-C 6烷基、砜、亚砜、磺酰胺、亚磺酰胺、C 1-3的羧基和任选地被卤素取代的C 1-C 6烷氧基；
b)
Figure PCTCN2021112386-appb-000018
p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 6烷基、C 1-C 6烷氧基以及C 3-C 8环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，其中：所述杂环基任选地被选自卤素、羟基、氰基、C 1-C 6卤代烷基和C 1-C 6烷基的一个或多个取代基取代；并且在
Figure PCTCN2021112386-appb-000019
中，当p为0时，R 9和R 10的组合不为氢和甲基；
c)
Figure PCTCN2021112386-appb-000020
d)杂环基和杂芳基，所述的杂环基和杂芳基各自任选地被选自氧代、卤素、羟基、羰基、C 1-C 6烷基和氰基的一个或多个取代基取代，所述的C 1-C 6烷基任选地被一个或多个卤素取代；和
e)
Figure PCTCN2021112386-appb-000021
其中，R 11选自C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、C 3-C 8环烃基、杂环基、C 1-C 6氰代烷基、C 3-C 8环烃基氧基和任选被C 1-C 6烷基取代的氨基；或者
R 7和R 8与其共同连接的原子一起形成任选被取代的芳香或非芳香杂环；
m为1-3的整数；且
n为1-4的整数。
在一些实施方案中，式(I)化合物中，
R 1选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 2各自独立地选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 3和R 4各自独立地选自氢、卤素和任选地被卤素取代的C 1-C 4烷基，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
R 6各自独立地选自氢、氘、卤素、氰基、环丙基和任选地被卤素或氘取代的C 1-C 6烷基；
R 7为任选地被选自甲基、氟原子、氯原子、卤代甲基和氰基的一个或多个取代基取代的以下基团：
Figure PCTCN2021112386-appb-000022
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基；
X选自氧原子、-NH-和亚甲基，所述亚甲基任选地被选自卤素、C 3-C 8环烃基、C 3-C 6亚环烃基和C 1-C 6烷基的一个或多个取代基取代；
m为1-3的整数；且
n为1-4的整数。
在一些实施方案中，式(I)化合物中，
R 1选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 2各自独立地选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 3和R 4各自独立地选自氢、卤素和任选地被卤素取代的C 1-C 4烷基，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的 C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
R 7和R 8与其共同连接的原子一起形成杂环A
Figure PCTCN2021112386-appb-000023
杂环A选自以下结构：
Figure PCTCN2021112386-appb-000024
R 6各自独立地选自氢、氘、卤素和氰基；
R 12各自独立地选自卤素、C 1-C 3烷基和C 3-C 6亚环烃基，或者相邻的R 12一起形成环，所述的环任选地被一个或多个卤素或C 1-C 3烷基取代；
m为1-3的整数；
n为1-3的整数；且
q为0-6的整数。
在一些实施方案中，式(I)化合物中，
R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 3和R 4各自独立地为氢或卤素，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基；
R 5为C 1-C 6烷基或C 1-C 6烷氧基；
R 7和R 8与其共同连接的原子一起形成杂环A
Figure PCTCN2021112386-appb-000025
杂环A选自以下结构：
Figure PCTCN2021112386-appb-000026
R 6各自独立地选自氢、氘、卤素和氰基；
m为1-3的整数；且
n为1-3的整数。
在一些实施方案中，式(I)化合物中，
R 1选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 2各自独立地选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 3和R 4各自独立地选自氢、卤素和任选地被卤素取代的C 1-C 4烷基，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
R 6各自独立地选自氢、氘、卤素、氰基、环丙基和任选地被卤素或氘取代的C 1-C 6烷基；
R 7选自以下基团：
Figure PCTCN2021112386-appb-000027
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基；
X选自氧原子、-NH-和亚甲基，所述亚甲基任选地被选自卤素、C 3-C 8环烃基、C 3-C 6亚环烃基和C 1-C 6烷基的一个或多个取代基取代；
m为1-3的整数；且
n为1-4的整数。
在一些实施方案中，式(I)化合物中，
R 1选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 2各自独立地选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
R 3和R 4各自独立地选自氢、卤素和任选地被卤素取代的C 1-C 4烷基，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
R 6各自独立地选自氢、氘、卤素、氰基、环丙基和任选地被卤素或氘取代的C 1-C 6烷基；
R 7选自以下基团：
Figure PCTCN2021112386-appb-000028
Figure PCTCN2021112386-appb-000029
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基；
X选自氧原子、-NH-和亚甲基，所述亚甲基任选地被选自卤素、C 3-C 8环烃基、C 3-C 6亚环烃基和C 1-C 6烷基的一个或多个取代基取代；
m为1-3的整数；且
n为1-4的整数。
本公开还提供如式(I-1)化合物、或其可药用盐、或其异构体，
Figure PCTCN2021112386-appb-000030
其中，R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 5为C 1-C 3烷基或C 1-C 3烷氧基；
R 6a和R 6b各自独立地选自氢、氘、氯原子、氟原子和氰基；
R 7为4-6元杂环基，所述杂环基包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环基任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基取代，所述的C 1-C 3烷基任选地被一个或多个卤素取代；
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基；且
m为1-3的整数。
在一些实施方案中，式(I-1)化合物中R 7为任选地被选自甲基、氟原子、氯原子、卤代甲基和氰基的一个或多个取代基取代的以下基团：
Figure PCTCN2021112386-appb-000031
Figure PCTCN2021112386-appb-000032
且
R 8选自氢、氘、卤素和氰基。
本公开还提供如式(I-1)化合物、或其可药用盐、或其异构体，
Figure PCTCN2021112386-appb-000033
其中，R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 5为C 1-C 3烷基或C 1-C 3烷氧基；
R 6a和R 6b各自独立地选自氢、氘、氯原子、氟原子和氰基；
R 7和R 8与其共同连接的原子一起形成4-8元非芳香杂环，所述杂环为单环或双环，所述杂环包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环任选被选自C 1-C 3烷基酰胺、卤素、氧代、任选地被卤素取代的C 1-C 3烷基和C 1-C 3烷氧基的一个或多个取代基取代；且
m为1-3的整数。
在一些实施方案中，式(I-1)化合物中R 7和R 8与其共同连接的原子一起形成杂环A
Figure PCTCN2021112386-appb-000034
杂环A选自以下结构：
Figure PCTCN2021112386-appb-000035
Figure PCTCN2021112386-appb-000036
R 6a和R 6b各自独立地选自氢、氘、氯原子和氟原子；
R 12各自独立地选自卤素、C 1-C 3烷基和C 3-C 6亚环烃基，或者相邻的R 12一起形成环，所述的环任选地被一个或多个卤素或C 1-C 3烷基取代；且
q为0-6的整数。
在一些实施方案中，式(I-1)化合物中R 7和R 8与其共同连接的原子一起形成杂环A
Figure PCTCN2021112386-appb-000037
杂环A选自以下结构：
Figure PCTCN2021112386-appb-000038
且
R 6a和R 6b各自独立地选自氢、氘、氯原子和氟原子。
本公开还提供如式(I-1)化合物、或其可药用盐、或其异构体，
Figure PCTCN2021112386-appb-000039
其中，R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 5为C 1-C 3烷基或C 1-C 3烷氧基；
R 6a和R 6b各自独立地选自氢、氘、氯原子、氟原子和氰基；
R 7为
Figure PCTCN2021112386-appb-000040
p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 3烷基、C 1-C 3烷氧基和C 3-C 6环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被选自卤素、羟基和C 1-C 3烷基的一个或多个取代基取代；
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基；且
m为1-3的整数。
在一些实施方案中，式(I-1)化合物中R 7选自以下基团：
Figure PCTCN2021112386-appb-000041
且
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基。
本公开还提供如式(I-1)化合物、或其可药用盐、或其异构体，
Figure PCTCN2021112386-appb-000042
其中，R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
R 5为C 1-C 3烷基或C 1-C 3烷氧基；
R 6a和R 6b各自独立地选自氢、氘、氯原子、氟原子和氰基；
R 7为
Figure PCTCN2021112386-appb-000043
p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 3烷基、C 1-C 3烷氧基和C 3-C 6环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被选自卤素、羟基和C 1-C 3烷基的一个或多个取代基取代；R’选自氢、C 1-C 3烷基、C 3-C 6环烃基、芳基和杂芳基；
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基；且
m为1-3的整数。
在一些实施方案中，式(I-1)化合物中R 7选自以下基团：
Figure PCTCN2021112386-appb-000044
且
R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基。
本公开还提供如下所示的化合物、或其可药用盐、或其异构体，
Figure PCTCN2021112386-appb-000045
Figure PCTCN2021112386-appb-000046
本公开提供一种制备式(I)化合物或其可药用盐、或其异构体的方法，包括如下步骤：
Figure PCTCN2021112386-appb-000047
式(I-a)所示的化合物与式(I-b)所示化合物在碱性条件下反应得到式(I-c)所示化合物；式(I-c)所示化合物经还原反应得到式(I-d)所示化合物；式(I-d)所示化合物与式(I-e)所示化合物在酸性条件下经关环反应得到式(I)所示化合物；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、X、m和n如式(I)化合物定义；且Y选自卤素、磺酰基和亚磺酰基。
本公开还提供另一种制备式(I)化合物或其可药用盐、或其异构体的方法，包括如下步骤：
Figure PCTCN2021112386-appb-000048
式(I-a)所示的化合物与式(I-b)所示化合物在碱性条件下反应得到式(I-c)所示化合物；式(I-c)所示化合物经还原反应得到式(I-d)所示化合物；式(I-d)所示化合物与式(I-f)所示化合物在酸性条件下经关环反应得到式(I-g)所示化合物；式(I-g)所示化合物在催化剂作用下反应得到式(I)所示化合物；
所述催化剂选自钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1'-双(二苄基磷)二氯二戊铁钯、三(二亚苄基丙酮)二钯、2-双环己基膦-2',6'-二甲氧基联苯、[1,1'-双(二-叔丁基膦基)二茂铁]二氯合钯(II)、碘化亚铜、溴化亚铜、氯化亚铜和三氟甲磺酸铜；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、X、m和n的定义如式I所示化合物中定义；且
Y和Z各自独立地选自卤素、磺酰基和亚磺酰基。
本公开还提供所述化合物或其可药用盐、或其异构体的制备方法。特别是采用实施例的方法进行制备。
本公开还涉及一种药物组合物，包含本公开所述的化合物或其可药用盐、或其异构体。一般来说，所述组合物还包含至少一种药学上可接受的载体、稀释剂或者赋形剂。
在一些实施方案中，所述药物组合物中，所述的的化合物或其可药用盐、或其异构体的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用的盐。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
本公开还涉及所述的化合物或其可药用盐、或其异构体，或者包含其的药物组合物在制备治疗与P2X3活性相关的疾病的药物中的用途。
本公开还涉及所述的化合物或其可药用盐、或其异构体，或者包含其的药物组合物，其用作药物。
本公开还涉及所述的化合物或其可药用盐、或其异构体，或者包含其的药物组合物，其用于治疗与P2X3活性相关的疾病。
本公开还涉及一种治疗与P2X3活性相关的疾病的方法，其包括给予所需患者治疗有效量的所述的化合物或其可药用盐、或其异构体，或者包含其的药物组合物。
在一些实施方案中，所述的P2X3活性相关的疾病指的是P2X3过度活性相关的疾病。本公开的化合物对P2X3具有高度选择性，可以避免味觉丧失。在一些实施方案中，本公开的化合物对P2X3同源受体拮抗作用比对P2X2/3异聚体受体拮抗作用强20倍以上。在一些实施方案中，本公开的化合物对P2X3同源受体拮抗作用比对P2X2/3异聚体受体拮抗作用强30倍以上。在一些实施方案中，本公开 的化合物对P2X3同源受体拮抗作用比对P2X2/3异聚体受体拮抗作用强50倍以上。在一些实施方案中，本公开的化合物对P2X3同源受体拮抗作用比对P2X2/3异聚体受体拮抗作用强100倍以上。
本公开还涉及所述的的化合物或其可药用盐、或其异构体，或者包含其的药物组合物在制备用于治疗疼痛、泌尿道疾病、咳嗽等疾病的药物中的用途。
本公开还涉及所述的化合物或其可药用盐、或其异构体，或者包含其的药物组合物，其用于治疗疼痛、泌尿道疾病、咳嗽等疾病。
本公开还涉及一种治疗疼痛、泌尿道疾病、咳嗽等疾病的方法，其包括给予所需患者治疗有效量的所述的化合物或其可药用盐、或其异构体，或者包含其的药物组合物。
在一些实施方案中，疼痛可以是例如慢性疼痛、神经性疼痛、急性疼痛、背痛、癌症疼痛、由类风湿性关节炎所引起的疼痛、偏头痛、以及内脏疼痛。泌尿道病症，例如膀胱过度活动症(也被称为尿失禁)、骨盆超敏反应、以及尿道炎。
在一些实施方案中，本公开的化合物或其可药用盐、或其异构体，或者包含其的药物组合物可用于治疗胃肠病症，包括例如便秘和功能性胃肠病症(例如肠易激综合征或功能性消化不良)；可以用于治疗癌症；可以用于治疗心血管病症或用于心肌梗塞后的心脏保护；可以用作免疫调节剂，特别是用于治疗自身免疫性疾病(例如关节炎)，用于皮肤移植、器官移植、或类似的手术需要，用于胶原病，用于过敏，或用作抗肿瘤剂或抗病毒剂；可以用于治疗多发性硬化、帕金森氏病(Parkinson's disease)以及亨廷顿氏舞蹈病(Huntington's chorea)；可以用于治疗抑郁症、焦虑、应激相关病症(例如创伤后应激病症、恐慌症、社交恐惧症、或强迫症)、早泄、精神病、创伤性脑损伤、中风、阿尔茨海默氏病(Alzheimer's disease)、脊椎损伤、药物成瘾(例如治疗酒精、尼古丁、阿片类物质、或其它药物滥用)、或交感神经系统病症(例如高血压)；可以用于治疗腹泻；可以用于治疗肺部病症，例如像哮喘、咳嗽或肺水肿。
本公开的化合物或其可药用盐、或其异构体可制成适合口服、颊面、阴道、直肠、经由吸入、经由吹入、鼻内、舌下、局部或肠胃外(例如肌内、皮下、腹膜内、胸内、静脉内、硬膜外、鞘内、侧脑室内或通过注射到关节内)施用的剂型。
本公开中所述化合物可药用盐可选自无机盐或有机盐。
术语“治疗”指为预防和/或治疗目的而给予药物组合物。对于“预防疾病”指预防性治疗尚未得病，但对特定疾病易感，或者面临特定疾病风险的受试者。对于“治疗疾病”指对已经罹患疾病的患者进行治疗以改善或稳定患者的病症。
本公开所述化合物或其可药用盐、或其异构体的任何同位素标记的(或“放射性标记的”)衍生物都被本公开所覆盖。这种衍生物是其中一个或多个原子被原子质量或质量数不同于通常在自然界中所发现的原子质量或质量数的原子置换。可以被掺入的放射性核素的实例包括 2H(也被写成“D”，即氘)、 3H(也被写成“T”，即氚)、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 18F、 36Cl、 82Br、 75Br、 76Br、 77Br、 123I、 124I、 125I、 31P、 32P、 35S、以及 131I。所使用的放射性核素将取决于该放射性标记的衍生物的具体应用。举例来说，对于体外受体标记和竞争测定， 3H或 14C常常是有用的。对于放射成像应用， 11C或 18F常常是有用的。在一些实施方案中，放射性核素是 3H。在一些实施方案中，放射性核素是 14C。在一些实施方案中，放射性核素是 11C。并且在一些实施方案中，放射性核素是 18F。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少3000倍的丰度的氘(即，至少45％的氘掺入)。
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
本公开所述化合物的化学结构中，键
Figure PCTCN2021112386-appb-000049
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021112386-appb-000050
可以为
Figure PCTCN2021112386-appb-000051
或者同时包含
Figure PCTCN2021112386-appb-000052
两种构型。本公开所述化合物的化学结构中，键
Figure PCTCN2021112386-appb-000053
并未指定构型，即键
Figure PCTCN2021112386-appb-000054
的构型可以为E型或Z型，或者同时包含E和Z两种构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2021112386-appb-000055
“卤素”是指氟，氯，溴和碘。
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
“烷基”是指直链或支链烷基，包括1至20个碳原子的直链和支链基团。优选包含1至6个碳原子，更优选包含1至3个碳原子，例如甲基、乙基、正丙基、异丙基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，，优选一个或多个以下基团，独立地选自卤素、羟基、氧代、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基、6至10芳基或5至10杂芳基，所述烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选被一个或多个卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基所取代。“烷氧基”是指烷基氧基，其中烷基如上所定义，例如甲氧基、乙氧基等。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基被一个或多个选自卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基取代。
“杂环基”是指包含1至6个杂原子、3至18个环原子的非芳香环基团，其中杂原子选自氧、氮和硫。杂环基优选包含1至4个杂原子，更优选包含1至3个杂原子，甚至更优选包含1个或2个杂原子；杂环基优选为3至12元，更优选为3至8元或4至8元，甚至更优选为4至6元，进一步更优选为5元或6元。除非本说明书中特别指明，杂环基可以是单环、二环、三环或四环体系，其可以包括螺环或桥环体系；并且杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；以及杂环基可部分或完全饱和。“包含-NH-C(＝O)-或者-NH-S(＝O) 2-的杂环基”环状结构上除“-NH-C(＝O)-”及“-NH-S(＝O) 2-”部分之外，其他部分任选地包含杂原子。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。
“杂芳基”指包含1至4个杂原子、5至14个环原子的芳香环基团，其中杂原子选自氧、硫和氮。杂芳基优选为4至6元或6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪，
Figure PCTCN2021112386-appb-000056
等等。
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、 杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
芳基或杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基被一个或多个选自卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基取代。
“环烃基”或“环烷基”是指仅由碳原子和氢原子构成的稳定的非芳香单环或多环烷基，其可以包含螺环或桥环体系，具有3至15个碳原子、3至10个碳原子、3至8个碳原子、3至6个碳原子、或者5至7个碳原子，并且其是饱和或不饱和的，并通过单键与分子其余部分连接。单环环烃基包括非桥环烷基，例如环丙基、环丁基、环戊基、环己基、环庚基和环辛基。环烷基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基被一个或多个选自卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基取代。“亚环烃基”或“亚环烷基”是指衍生自环烃基的二价环烃基。例如，
Figure PCTCN2021112386-appb-000057
等。可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基被一个或多个选自卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基取代。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选地被卤素或者氰基取代的C 1-C 6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氰基”指-CN。
术语“氨基”指-NH 2。
术语“硝基”指-NO 2。
术语“氧代”指＝O取代基。
术语“羧基”指-C(O)OH。
“取代的”指基团中的一个或多个氢原子，优选为1-5个，更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。
“可药用盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受 的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
具体实施方式
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)和氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
HPLC的测定使用Waters ACQUITY ultra high performance LC、Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200 LC高压液相色谱仪(ACQUITY UPLC BEH C18 1.7μm 2.1*50mm色谱柱、Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
MS的测定用Waters SQD2质谱仪，以正/负离子模式扫描，质量扫描范围为100-1200。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.，3μm、Chiralpak AD-3 150×4.6mm I.D.，3μm、Chiralpak AD-3 50×4.6mm I.D.，3μm、Chiralpak AS-3 150×4.6mm I.D.，3μm、Chiralpak AS-3 100×4.6mm I.D.，3μm、ChiralCel OD-3 150×4.6mm I.D.，3μm、ChiralCel OD-3 100×4.6mm I.D.，3μm、ChiralCel OJ-H 150×4.6mm I.D.，5μm、ChiralCel OJ-3 150×4.6mm I.D.，3μm色谱柱。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10μm)或Phenomenex-Amylose-1(250mm*30mm,5μm)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛围或氮气氛围下进行。
氩气氛围或氮气氛围是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛围是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
阳性化合物MK-7264的制备参考专利WO2005095359的实验步骤。
实施例1
1-[4-(1-{[(2R)-4-乙酰基吗啉-2-基]甲基}-5-甲基-1H-1,3-苯并二唑-2-基)-3,5-二氟苯基]吡咯烷-2-酮(1)
Figure PCTCN2021112386-appb-000058
步骤一：叔丁基(2S)-2-[(1,3-二羰基-2,3-二氢-1H-异吲哚-2-基)甲基]吗啉-4-羧酸酯(1a)
将(2R)-2-(羟甲基)吗啉-4-羧酸叔丁酯(3.00g,13.81mmol)、2,3-二氢-1H-异吲哚-1,3-二酮(2.23g,15.19mmol)和三苯基膦(5.43g,20.71mmol)溶于THF(50mL)中，在0℃和氮气保护下滴加偶氮二羧酸二异丙酯(4.1mL,20.71mmol)。待反应混合物在室温下搅拌12小时后，LCMS显示原料反应完全。将混合物在减压下浓缩，残余物用快速硅胶色谱纯化(乙酸乙酯/石油醚＝0-30％,60mL/min)得到标题化合物1a(6.00g,产率：87.8％)。
MS(ESI)m/z＝291.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.83-7.76(m,2H),7.69-7.63(m,2H),4.91(spt,J＝6.2Hz,3H),3.96-3.84(m,1H),3.83-3.77(m,2H),3.75-3.64(m,2H),3.60(dd,J＝4.6,13.6Hz,1H),3.37(dt,J＝2.9,11.4Hz,1H),2.92(br s,1H),2.69(br s,1H),1.39(s,9H),1.21(s,11H)。
步骤二：叔丁基(2S)-2-(氨基甲基)吗啉-4-羧酸酯(1b)
室温下，向化合物1a(6.00g,12.12mmol)的乙醇(150mL)溶液中加入水合肼(1.07g,18.19mmol)，然后反应混合物在80℃下搅拌1小时，LCMS显示反应完成。将混合物冷却至室温，过滤、减压浓缩滤液。将残余物溶于乙酸乙酯(80mL)中并过滤，滤液减压浓缩得到标题化合物1b(3.00g，产率：91.5％)。
1H NMR(400MHz,CDCl 3)δ6.27(br s,2H),3.82(br d,J＝10.9Hz,3H),3.51-3.41(m,1H),3.34-3.23(m,1H),3.29(br dd,J＝3.7,6.7Hz,1H),2.85(br s,1H),2.73-2.63(m,2H),2.57(br s,1H),1.40(s,9H)。
步骤三：叔丁基(2S)-2-{[(4-甲基-2-硝基苯基)氨基]甲基}吗啉-4-羧酸酯(1c)
室温下，向化合物1b(3.00g,11.10mmol)的1,4-二氧六环(60mL)溶液中加入1-氟-4-甲基-2-硝基苯(1.72g,11.10mmol)和乙基二异丙基胺(3.7mL,22.19mmol)，然后反应混合物在100℃下搅拌12小时。LCMS显示原料消失完全。加入水(50mL)，用乙酸乙酯(80mL×3)萃取。合并的有机相经无水硫酸钠干燥，过滤并减压浓缩，得到粗产品经快速硅胶色谱纯化(乙酸乙酯/石油醚＝0-17％,60mL/min)得到标题化合物1c(2.35g,产率：60％)。
MS(ESI)m/z＝374.2[M+Na] +。
1H NMR(400MHz,CDCl 3)δ8.11(br s,1H),7.99(d,J＝0.8Hz,1H),7.30-7.27(m,1H),6.77(d,J＝8.8Hz,1H),4.06-3.81(m,3H),3.75-3.65(m,1H),3.64-3.53(m,1H),3.47-3.29(m,2H),3.09-2.91(m,1H),2.80(br s,1H),2.28(s,3H),1.47(s,9H)。
步骤四：叔丁基(2S)-2-{[(2-氨基-4-甲基苯基)氨基]甲基}吗啉-4-羧酸酯(1d)
室温下，向化合物1c(2.00g,5.69mmol)的甲醇(20mL)溶液中加入10％Pd/C(100mg)。将所得混合物用氢气置换3次，然后反应混合物在室温下搅拌12小时。LCMS显示原料消失完全。过滤混合物并将滤液真空浓缩，得到标题化合物1d(1.73 g,产率：94.4％)。
MS(ESI)m/z＝322.2[M+H] +。
1H NMR(400MHz,CDCl 3):δ6.65-6.50(m,3H),3.92(br d,J＝10.0Hz,3H),3.70-3.62(m,1H),3.60-3.51(m,1H),3.44(br s,2H),3.32-3.00(m,3H),2.97(br s,1H),2.79(br s,1H),2.23(s,3H),1.48(s,9H)。
步骤五：叔丁基(2S)-2-{[2-(4-溴-2,6-二氟苯基)-5-甲基-1H-1,3-苯并二唑-1-基]甲基}吗啉-4-羧酸酯(1e)
室温下，向化合物1d(810.0mg,2.52mmol)的正丁醇(14mL)溶液中加入4-溴-2,6-二氟苯甲醛(612.6mg,2.77mmol)和乙酸(144μL,2.52mmol)。将所得混合物用氮气置换3次，然后反应混合物在90℃下搅拌14小时。LCMS显示原料反应完全。然后将反应液真空浓缩，得到粗产物经硅胶快速色谱法(乙酸乙酯/石油醚＝0-17％)纯化得到标题化合物1e(189.8mg,产率：14.4％)。
MS(ESI)m/z＝524.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.63(br s,1H),7.37(br d,J＝7.6Hz,1H),7.26(br d,J＝6.0Hz,2H),7.19(br d,J＝7.2Hz,1H),4.10(br s,2H),3.88-3.53(m,4H),3.30(br s,1H),2.77(br s,1H),2.51(br s,3H),2.48-2.38(m,1H),1.42(br s,9H)。
步骤六：1-[4-(1-{[(2R)-4-乙酰基吗啉-2-基]甲基}-5-甲基-1H-1,3-苯并二唑-2-基)-3,5-二氟苯基]吡咯烷-2-酮(1)
室温下向化合物1e(90.0mg,0.172mmol)和吡咯烷-2-酮(29.3mg,0.345mmol)的1,4-二氧六环(3mL)溶液中加入Cs 2CO 3(112.3mg,0.345mmol)、Pd(OAc) 2(5.8mg,0.026mmol)和Xantphos(20.0mg,0.034mmol)。然后所得混合物用氮气鼓泡5分钟，在微波100℃下搅拌35分钟。LCMS显示反应完全。加入水(5mL)淬灭反应，用乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥并过滤。滤液减压浓缩得到的粗产物溶于二氯甲烷(2mL)，冰水浴下加入三氟乙酸(400μL)。反应混合物室温下搅拌1小时，LCMS显示反应完全。混合物减压浓缩，所得残余物溶于甲醇(2mL)，冰水浴下加入三乙胺(238μL,1.71mmol)调节pH至8，然后加入乙酸酐(80μL,0.854mmol)并在室温下反应1小时。LCMS显示反应完全，反应混合物浓缩后经C18反相色谱法(乙腈/水(含0.05％氨水)＝10-75％)纯化并冻干后得到标题化合物1(52.0mg,产率：64％)。
MS(ESI)m/z＝469.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ8.43(br d,J＝7.0Hz,1H),7.63(dd,J＝3.3,10.3Hz,2H),7.37(s,1H),6.93-6.73(m,1H),4.09(br dd,J＝9.2,18.9Hz,2H),3.99-3.85(m,3H),3.77-3.52(m,2H),3.51-3.41(m,2H),3.09-2.99(m,2H),2.90-2.82(m,1H),2.73-2.65(m,1H),2.63-2.58(m,2H),2.41(s,3H),2.18-2.03(m,2H)。
实施例2
甲基2-((2-(2,6-二氟-4-(2-羰基吡咯烷-1-基)苯基)-5-甲基-1H-苯并[d]咪唑-1-基)甲基)吗啉-4-羧酸酯(2)
Figure PCTCN2021112386-appb-000059
实施例2的合成步骤参见实施例1。其中步骤一中以2-(羟甲基)吗啉-4-羧酸叔丁酯替代(2R)-2-(羟甲基)吗啉-4-羧酸叔丁酯，步骤六中以氯甲酸甲酯替代乙酸酐。
MS(ESI)m/z＝486.4[M+H] +。
实施例3
(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-甲基-1H-苯并[d]咪唑-2-基)-3-氯苯基)吡咯烷-2-酮(3)
Figure PCTCN2021112386-appb-000060
实施例3的合成步骤参见实施例1。其中步骤五中以4-溴-2-氯苯甲醛替代4-溴-2,6-二氟苯甲醛。
MS(ESI)m/z＝467.2[M+H] +。
实施例4
(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-甲基-1H-苯并[d]咪唑-2-基)-3-氯-5-氟苯基)吡咯烷-2-酮(4)
Figure PCTCN2021112386-appb-000061
实施例4的合成步骤参见实施例1。其中步骤五中以4-溴-2-氯-6-氟苯甲醛替代4-溴-2,6-二氟苯甲醛。
MS(ESI)m/z＝485.5[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.88(br s,1H),7.79(br d,J＝11.6Hz,1H),7.70-7.60(m,1H),7.49(br s,1H),7.20-7.12(m,1H),4.33-4.16(m,2H),4.03(br d,J＝15.0Hz,1H),3.97-3.87(m,3H),3.78(br d,J＝17.6Hz,1H),3.68-3.55(m,1H),3.12(br d,J＝11.0Hz,1H),2.99(br d,J＝11.6Hz,1H),2.81-2.70(m,2H),2.58(br d,J＝7.9Hz,2H),2.44(br s,3H),2.14-2.06(m,2H),1.93(s,2H)。
实施例5
(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-(二氟甲基)-1H-苯并[d]咪唑-2-基)-3,5-二氟苯基)吡咯烷-2-酮(5)
Figure PCTCN2021112386-appb-000062
实施例5的合成步骤参见实施例1。其中步骤三中以4-(二氟甲基)-1-氟-2-硝基苯替代1-氟-4-甲基-2-硝基苯。
MS(ESI)m/z＝505.5[M+H] +。
实施例6
甲基(S)-2-((2-(2,6-二氟-4-(甲基氨基甲酰)苯基)-6-甲基-3H-咪唑并[4,5-b]吡啶-3-基)甲基)吗啉-4-羧酸酯(6)
Figure PCTCN2021112386-appb-000063
步骤一：甲基(R)-2-(羟甲基)吗啉-4-羧酸酯(6a)
室温下，向(2R)-2-(羟甲基)吗啉-4-羧酸叔丁酯(10.00g,46.03mmol)的甲醇(50mL)溶液中滴加4N HCl的甲醇溶液(57.5mL,230.13mmol)，然后反应混合物在室温下搅拌4小时。TLC(石油醚/乙酸乙酯＝3/1，样品经饱和NaHCO 3溶液处理)显示原料反应完全，减压浓缩。所得残余物溶于二氯甲烷(50mL)，冰水浴下依次缓慢滴加乙基二异丙基胺(38.0mL,230.13mmol)和氯甲酸甲酯(4.3mL,55.23mmol)。然后反应混合物在室温下搅拌2小时。TLC(石油醚/乙酸乙酯＝1/2)显示原料反应完全。加入水(100mL)淬灭反应，用乙酸乙酯(50mL×5)萃取。合并的有机相经无水硫酸钠干燥，过滤并减压浓缩，得到标题化合物6a(9.45g,产率：94％)。
1H NMR(400MHz,CDCl 3)δ4.02-3.85(m,3H),3.73(s,3H),3.69-3.66(m,1H),3.63-3.53(m,3H),3.05-2.92(m,1H),2.90-2.72(m,1H)。
步骤二：甲基(S)-2-((1,3-二羰基异二氢吲哚-2-基)甲基)吗啉-4-羧酸酯(6b)
化合物6b的合成步骤参见实施例1的步骤一。其中以化合物6a替代(2R)-2-(羟甲基)吗啉-4-羧酸叔丁酯。
MS(ESI)m/z＝305.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.91-7.84(m,2H),7.77-7.71(m,2H),3.99(br s,1H),3.93-3.87(m,2H),3.82-3.80(m,1H),3.77(br s,1H),3.71(s,3H),3.70-3.64(m,1H),3.47(dt,J＝2.4,11.2Hz,1H),3.04(br s,1H),2.83(br t,J＝11.6Hz,1H)。
步骤三：甲基(S)-2-(氨基甲基)吗啉-4-羧酸酯(6c)
化合物6c的合成步骤参见实施例1的步骤二。其中以化合物6b替代化合物1a。
1H NMR(400MHz,CDCl 3)δ3.91(br d,J＝9.2Hz,3H),3.72(s,3H),3.61-3.48(m,1H),3.37(br d,J＝2.4Hz,1H),2.99(br s,1H),2.76(br d,J＝6.4Hz,1H),2.74-2.63(m,1H)。
步骤四：甲基(S)-2-(((5-甲基-3-硝基吡啶-2-基)氨基)甲基)吗啉-4-羧酸酯(6d)
室温下，向2-氯-5-甲基-3-硝基吡啶(200.0mg,1.16mmol)和化合物6c(356.2mg,1.39mmol)的二甲基亚砜(2mL)溶液中加入乙基二异丙基胺(0.57mL,3.48mmol)，然后反应混合物在60℃下搅拌12小时。LCMS显示原料消失完全。加入乙酸乙酯(30mL)稀释，过滤，滤液减压浓缩，得到粗产品经快速硅胶色谱纯化(乙酸乙酯/石油醚＝0-50％)得到标题化合物6d(237.2mg,产率：66％)。
MS(ESI)m/z＝310.9[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.42-8.19(m,3H),4.09-3.83(m,3H),3.73(s,3H),3.70-3.51(m,3H),3.11-2.93(m,1H),2.89-2.69(m,1H),2.28(s,3H)。
步骤五：甲基(S)-2-(((3-氨基-5-甲基吡啶-2-基)氨基)甲基)吗啉-4-羧酸酯(6e)
化合物6e的合成步骤参见实施例1的步骤四。其中以化合物6d替代化合物1c。
1H NMR(400MHz,CDCl 3)δ7.55(s,1H),6.71(s,1H),4.31(br s,1H),4.07-3.82(m,J＝12.8Hz,3H),3.72(s,3H),3.71-3.63(m,2H),3.61-3.51(m,1H),3.44-3.31(m,1H),3.21(br s,2H),3.06-2.96(m,1H),2.86-2.75(m,1H),2.16(s,3H)。
步骤六：甲基(S)-2-((2-(2,6-二氟-4-(甲基氨基甲酰)苯基)-6-甲基-3H-咪唑并[4,5-b]吡啶-3-基)甲基)吗啉-4-羧酸酯(6)
化合物6的合成步骤参见实施例1的步骤五。其中以化合物6e替代化合物1d，以3,5-二氟-4-甲酰基-N-甲基苯酰胺替代4-溴-2,6-二氟苯甲醛。
MS(ESI)m/z＝460.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.32(s,1H),7.92(s,1H),7.53(br s,1H),7.45(br d,J＝8.8Hz,2H),4.36(dd,J＝3.2,14.4Hz,1H),4.16(br dd,J＝7.6,14.4Hz,1H),3.98(br s,1H),3.83-3.69(m,1H),3.66(s,3H),3.65-3.61(m,1H),3.57(br d,J＝10.8Hz,1H),3.23(br t,J＝10.8Hz,1H),3.03(d,J＝4.4Hz,3H),2.76(br s,1H),2.53(s,3H),2.47(br s,1H)。
实施例7
甲基(S)-2-((2-(2,6-二氟-4-(甲基氨基甲酰)苯基)-5-甲基-1H-咪唑并[4,5-b]吡啶-1-基)甲基)吗啉-4-羧酸酯(7)
Figure PCTCN2021112386-appb-000064
步骤一：6-甲基-2-硝基吡啶-3-基三氟甲磺酸(7a)
在0℃和氮气保护下，向6-甲基-2-硝基吡啶-3-醇(1.00g,6.50mmol)的二氯甲烷(10mL)溶液中加入三乙胺(1.4mL,9.70mmol)和三氟甲磺酸酐(1.3mL,7.80mmol)。所得溶液在0℃下搅拌2小时。加入水(80mL)淬灭反应，并用乙酸乙酯(50mL×3)萃取。合并的有机层用盐水(80mL×3)洗涤，用无水硫酸钠干燥，过滤，并在减压下浓缩得到标题化合物7a(1.70g,收率：92％)。
1H NMR(400MHz,CDCl 3)δ7.82(d,J＝8.4Hz,1H),7.60(d,J＝8.4Hz,1H),2.70(s,3H)。
步骤二：甲基(S)-2-(((6-甲基-2-硝基吡啶-3-基)氨基)甲基)吗啉-4-羧酸酯(7b)
室温下，向化合物7a(1.20g,4.2mmol)和化合物6c(870mg,3.5mmol)的乙腈(15mL)溶液中滴加三乙胺(1.10g,10.5mmol)。将所得溶液在80℃下搅拌12小时。LCMS显示原料消失完全。减压浓缩，得到的粗产物经反相C18柱色谱法(甲醇/水溶液(0.1％TFA)＝50％)纯化并冻干，得到标题化合物7b(275.0mg,产率：25％)。
MS(ESI)m/z＝310.9[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.92-7.80(m,1H),7.35-7.29(m,2H),3.74(s,3H),3.63-3.52(m,3H),3.51-3.40(m,2H),3.39-3.32(m,1H),3.25(dd,J＝7.6,13.2Hz,1H),3.11-2.93(m,2H),2.52(s,3H)。
步骤三：甲基(S)-2-(((2-氨基-6-甲基吡啶-3-基)氨基)甲基)吗啉-4-羧酸酯(7c)
化合物7c的合成步骤参见实施例1的步骤四。其中以化合物7b替代化合物1c。
MS(ESI)m/z＝280.9[M+H] +。
1H NMR(400MHz,CDCl 3)δ6.75(d,J＝8.0Hz,1H),6.53(d,J＝7.6Hz,1H),3.74(s,3H),3.61-3.53(m,3H),3.46(dd,J＝3.6,13.6Hz,1H),3.25(dd,J＝7.6,13.6Hz,1H),3.11-3.02(m,2H),2.91-2.69(m,2H),2.34(s,3H)。
步骤四：甲基(S)-2-((2-(2,6-二氟-4-(甲基氨基甲酰)苯基)-5-甲基-1H-咪唑并[4,5-b]吡啶-1-基)甲基)吗啉-4-羧酸酯(7)
化合物7的合成步骤参见实施例1的步骤五。其中以化合物7c替代化合物1d，以3,5-二氟-4-甲酰基-N-甲基苯酰胺替代4-溴-2,6-二氟苯甲醛。
MS(ESI)m/z＝460.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.91(br s,1H),7.78(d,J＝6.4Hz,1H),7.52(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,1H),4.17-3.98(m,2H),3.95-3.59(m,6H),3.59-3.46(m,1H),3.36-3.18(m,1H),3.05(d,J＝4.8Hz,3H),2.86-2.77(m,1H),2.75(s,3H),2.56-2.42(m,1H)。
实施例8
甲基(S)-2-((2-(2,6-二氟-4-(甲基氨基甲酰)苯基)-6-甲基-3H-咪唑并[4,5-c]吡啶-3-基)甲基)吗啉-4-羧酸酯(8)
Figure PCTCN2021112386-appb-000065
步骤一：(S)-5-(((4-(甲氧羰基)吗啉-2-基)甲基)氨基)-2-甲基-4-硝基吡啶1-氧化物(8a)
室温下，将5-溴-2-甲基-4-硝基吡啶1-氧化物(200.0mg,0.86mmol)和化合物6c(329.0mg,1.89mmol)溶于四氢呋喃(5mL)，并将所得溶液在80℃下搅拌12小时。LCMS显示原料消失完全。减压浓缩，得到的粗产物加入甲醇(2mL)，过滤后的固体经干燥得到标题化合物8a(50.0mg,产率：18％)。
MS(ESI)m/z＝327.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.06(s,1H),8.01(s,1H),7.90-7.80(m,1H),4.23-3.81(m,4H),3.74(s,3H),3.61-3.55(m,1H),3.42-3.35(m,1H),3.32-3.24(m,1H),3.14-3.00(m,2H),2.41(s,3H)。
步骤二：甲基(S)-2-(((4-氨基-6-甲基吡啶-3-基)氨基)甲基)吗啉-4-羧酸酯(8b)
化合物8b的合成步骤参见实施例1的步骤四。其中以化合物8a替代化合物1c。
MS(ESI)m/z＝281.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),6.46(s,1H),4.03-3.81(m,4H),3.73(s,3H),3.69-3.53(m,3H),3.16-3.07(m,2H),2.40(s,3H)。
步骤三：甲基(S)-2-((2-(2,6-二氟-4-(甲基氨基甲酰)苯基)-6-甲基-3H-咪唑并[4,5-c]吡啶-3-基)甲基)吗啉-4-羧酸酯(8)
化合物8的合成步骤参见实施例1的步骤五。其中以化合物8b替代化合物1d，以3,5-二氟-4-甲酰基-N-甲基苯酰胺替代4-溴-2,6-二氟苯甲醛。
MS(ESI)m/z＝460.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.87(s,1H),7.58(s,1H),7.49(d,J＝8.4Hz,2H),6.92-6.75(m,1H),4.25-4.09(m,2H),3.98-3.71(m,3H),3.69(s,3H),3.65-3.55(m,1H),3.36-3.25(m,1H),3.06(d,J＝4.8Hz,3H),2.90-2.77(m,1H),2.72(s,3H),2.60-2.46(m,1H)。
实施例9
甲基(S)-2-((2-(2,6-二氟-4-(2-羰基吡咯烷-1-基)苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-羧酸酯(9)
Figure PCTCN2021112386-appb-000066
步骤一：叔丁基(2R)-2-甲酰基吗啉-4-羧酸酯(9a)
在-70℃和氮气保护下，向草酰氯(9.9mL,115.07mmol)的无水二氯甲烷(200mL)溶液中滴加二甲基亚砜(9.8mL,138.08mmol)。将混合物在-70℃下搅拌30分钟。滴加(2R)-2-(羟甲基)吗啉-4-羧酸叔丁酯(10.00g,46.03mmol)的二氯甲烷(30mL)溶液，并将混合物在-70℃下搅拌2小时。在-70℃下滴加三乙胺(32.0mL,230.13mmol)，并将混合物在-70℃下搅拌30分钟。TLC(石油醚/乙酸乙酯＝1/1)显示反应完成。该混合物恢复至室温后，用饱和NaHCO 3溶液(80mL×2)和盐水(80mL)洗涤。有机层经无水硫酸钠干燥，过滤并减压浓缩，得到标题化合物9a(9.90g,产率：99.9％)。
1H NMR(400MHz,CDCl 3)δ9.67(s,1H),4.15-4.04(m,1H),3.95-3.82(m,2H),3.70-3.53(m,2H),3.13-2.97(m,2H),1.50(s,9H)。
步骤二：叔丁基(2R)-2-甲酰基吗啉-4-羧酸酯(9b)
在0℃和氮气保护下，向化合物9a(9.90g,45.99mmol)的甲醇(200mL)溶液中依次加入碳酸钾(25.43g,183.97mmol)和(1-重氮-2-氧代丙基)膦酸二甲酯(17.67g,91.99mmol)。将混合物在室温下搅拌12小时，TLC(石油醚/乙酸乙酯＝3/1)显示反应完全。向混合物中加入水(80mL)，并在减压下浓缩以除去甲醇。将残余物用乙酸乙酯(100mL×3)萃取。合并的有机层经无水硫酸钠干燥，过滤并在减压下浓缩。残余物用快速硅胶色谱(乙酸乙酯/石油醚＝0-25％)纯化得到化合物9b(6.4g,产率：65.9％)。
1H NMR(400MHz,CDCl 3)δ4.29-4.25(m,1H),3.99-3.96(m,1H),3.93-3.63(m,1H),3.64-3.55(m,2H),3.33-3.27(m,2H),2.50(d,J＝2.4Hz,1H),1.49(s,9H)。
步骤三：甲基(S)-2-乙炔基吗啉-4-羧酸酯(9c)
室温下，向化合物9b(6.4g,30.29mmol)的二氯甲烷(60mL)溶液中滴加4N HCl的甲醇溶液(60mL,240.00mmol)，然后反应混合物在室温下搅拌12小时。TLC(石油醚/乙酸乙酯＝3/1)显示原料反应完全，减压浓缩。所得残余物溶于二氯甲烷(80mL)，冰水浴下依次缓慢滴加乙基二异丙基胺(14.8mL,89.43mmol)和氯甲酸甲酯(2.8mL,35.98mmol)。然后反应混合物在室温下搅拌12小时。TLC(石油醚/乙酸乙酯＝1/2)显示原料反应完全，反应液减压浓缩。所得残余物用快速硅胶色谱(乙酸乙酯/石油醚＝0-25％)纯化得到标题化合物9c(5.00g,产率：97.6％)。
1H NMR(400MHz,CDCl 3)δ4.31-4.28(m,1H),4.01-3.97(m,1H),3.90-3.82(m,1H),3.75(s,3H),3.68-3.56(m,2H),3.74-3.34(m,2H),2.52(d,J＝2.0Hz,1H)。
步骤四：甲基(S)-2-((2-(4-溴-2,6-二氟苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-羧酸酯(9d)
将化合物9c(7.5g,44.33mmol)、4-溴-2,6-二氟苯甲醛(9.80g,44.33mmol)和4-甲基吡啶-2-胺(4.79g,44.33mmol)溶于甲苯(75mL)，在氮气保护下加入氯化亚铜(1.32g,13.30mmol)和三氟甲磺酸铜(4.81g,13.30mmol)。将混合物在85℃下搅拌5分钟后，加入N,N-二甲基乙酰胺(1.2mL,13.30mmol)。反应混合物在85℃下搅拌12小时后，TLC显示原料消失完全。加入水(50mL)和氨水(30mL)。反应混合物用二氯甲烷(100mL×3)萃取，合并的有机相经无水硫酸钠干燥、过滤后，将滤液减压浓缩，得到的粗产物经硅胶柱色谱法纯化(乙酸乙酯/石油醚＝0-85％)，得到化合物9d(6.00g,产率：26.8％)。
MS(ESI)m/z＝480.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.17(d,J＝6.8Hz,1H),7.38(s,1H),7.25-7.18(m,2H),6.67(br d,J＝6.8Hz,1H),4.01-3.74(m,3H),3.68(s,3H),3.56(br s,1H),3.44-3.34(m,1H),3.06-2.85(m,3H),2.60(dd,J＝11.2,12.8Hz,1H),2.42(s,3H)。
步骤五：甲基(S)-2-((2-(2,6-二氟-4-(2-羰基吡咯烷-1-基)苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-羧酸酯(9)
在微波管中，向化合物9d(48.0mg,0.10mmol)的1,4-二氧六环(2mL)溶液中依次加入2-吡咯烷酮(34.0mg,0.40mmol)、N,N’-二甲基乙二胺(6μL,0.05mmol)、碳酸铯(195.5mg,0.60mmol)和碘化亚铜(9.5mg,0.05mmol)。将反应混合物在微波下加热至150℃持续反应1小时。LCMS显示反应完成。将反应混合物减压浓缩，残余物经乙腈溶解并过滤，滤液直接经C18反相色谱法(乙腈/水(含0.05％NH 3·H 2O)＝5-95％，流速：60mL/min)纯化并冻干后得到标题化合物9(26.0mg,产率：53.7％)。
MS(ESI)m/z＝485.3[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ8.40(d,J＝7.3Hz,1H),7.60(d,J＝10.0Hz,2H),7.34(s,1H),6.82(dd,J＝1.4,7.2Hz,1H),3.88(t,J＝7.2Hz,2H),3.75-3.60(m,3H),3.55(s,3H),3.46(br d,J＝7.3Hz,1H),3.28-3.19(m,1H),3.01(br d,J＝6.0Hz, 2H),2.80(br s,1H),2.57(t,J＝8.0Hz,3H),2.37(s,3H),2.08(quin,J＝7.6Hz,2H)。
实施例10
(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-氯-1H-苯并[d]咪唑-2-基)-3,5-二氟苯基)吡咯烷-2-酮(10)
Figure PCTCN2021112386-appb-000067
步骤一：(R)-2-((4-乙酰基吗啉-2-基)甲基)异二氢吲哚-1,3-二酮(10a)
将化合物1a(5.00g,14.44mmol)溶于4M HCl的1,4-二氧六环溶液(20mL)中，混合物在25℃下搅拌2小时。TLC(石油醚/乙酸乙酯＝1/1)显示反应完成。浓缩，残余物溶于四氢呋喃(30mL)中，冰水浴下加入三乙胺(9.8mL,70.74mmol)和乙酸酐(4.0mL,42.44mmol)并在室温下反应1.5小时。TLC(石油醚/乙酸乙酯＝1/1)显示反应完成。加入水(50mL)淬灭反应并用乙酸乙酯(50mL×3)萃取。合并的有机层经无水硫酸钠干燥，过滤并在减压下浓缩。残余物用快速硅胶色谱(乙酸乙酯/石油醚＝0-100％)纯化得到化合物10a(2.50g,产率：54.0％)。
MS(ESI)m/z＝314.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.88(br s,2H),7.75(br d,J＝5.4Hz,2H),4.55-4.28(m,1H),3.94(br d,J＝7.2Hz,2H),3.83-3.64(m,3H),3.60-3.42(m,1H),3.38-3.02(m,1H),2.93-2.61(m,1H),2.10(br d,J＝6.0Hz,3H)。
步骤二：(S)-1-(2-(氨基甲基)吗啉代)乙烷-1-酮(10b)
室温下，向化合物10a(1.00g,3.47mmol)的乙醇(6mL)溶液中加入水合肼(206μL,4.16mmol)，然后反应混合物在80℃下搅拌1小时，TLC(石油醚/乙酸乙酯＝1/1)显示反应完成。将混合物冷却至室温，过滤、减压浓缩滤液。将残余物溶于乙酸乙酯(20mL)中并过滤，滤液减压浓缩得到标题化合物10b(600.0mg，产率：98.4％)。
1H NMR(400MHz,CDCl 3)δ4.42-4.32(m,1H),3.95-3.87(m,1H),3.68-3.43(m,3H),3.42-3.18(m,2H),3.03-2.91(m,1H),2.88-2.57(m,3H),2.46(dd,J＝10.8,13.2Hz,1H),2.07(s,3H)。
步骤三：(S)-1-(2-(((4-氯-2-硝基苯基)氨基)甲基)吗啉代)乙烷-1-酮(10c)
室温下，向化合物10b(300.0mg,1.90mmol)的四氢呋喃(5mL)溶液中加入1-氟-4-氯-2-硝基苯(399.5mg,2.28mmol)和碳酸钾(523.0mg,3.79mmol)，然后反应混合物在25℃下搅拌2小时。LCMS显示原料消失完全。加入水(10mL)，用乙酸乙酯(15mL×3)萃取。合并的有机相经无水硫酸钠干燥，过滤并减压浓缩，得到粗产品经快速硅胶色谱纯化(乙酸乙酯/石油醚＝0-50％,35mL/min)得到标题化合物10c(300.0mg,产率：30.2％)。
MS(ESI)m/z＝314.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.27-8.15(m,2H),7.46-7.37(m,1H),6.89-6.79(m,1H),4.54(br d,J＝13.2Hz,1H),4.02(dd,J＝2.8,10.8Hz,1H),3.77-3.53(m,3H),3.51-3.28(m,3H),2.67(dd,J＝10.8,13.2Hz,1H),2.15-2.10(m,3H)。
步骤四：(S)-1-(2-(((2-氨基-4-氯苯基)氨基)甲基)吗啉代)乙烷-1-酮(10d)
室温下，向化合物10c(400.0mg,1.28mmol)的四氢呋喃(5mL)、乙醇(5mL)和水(5mL)混合溶液中加入氯化铵(675.7mg,12.75mmol)和铁粉(356.0mg,6.38mmol)。然后反应混合物在60℃下搅拌2小时。LCMS显示原料消失完全。过滤混合物并将滤液用乙酸乙酯(30mL×3)萃取，合并的有机相经无水硫酸钠干燥，过滤并减压浓缩，得到标题化合物10d(380.0mg,产率：94.5％)。
1H NMR(400MHz,CDCl 3)δ6.78-6.67(m,2H),6.57-6.51(m,1H),4.56-4.38(m,1H),4.03-3.93(m,1H),3.71-3.50(m,5H),3.36-3.25(m,1H),3.23-3.07(m,3H),2.87-2.60(m,1H),2.11(d,J＝3.2Hz,3H)。
步骤五：(S)-1-(2-((2-(4-溴-2,6-二氟苯基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)吗啉代)乙烷-1-酮(10e)
室温下，向化合物10d(190.0mg,0.67mmol)的正丁醇(5mL)溶液中加入4-溴-2,6-二氟苯甲醛(163.0mg,0.74mmol)和乙酸(238μL,1.34mmol)。所得混合物在90℃下搅拌12小时。LCMS显示原料反应完全。然后将反应液真空浓缩，得到粗产物经硅胶快速色谱法(石油醚/乙酸乙酯＝0-80％)纯化得到标题化合物10e(300.0mg,产率：83.1％)。
1H NMR(400MHz,CDCl 3)δ7.86-7.79(m,1H),7.46-7.40(m,1H),7.38-7.27(m,3H),4.50-4.31(m,1H),4.16-4.10(m,3H),3.85-3.70(m,1H),3.55-3.47(m,1H), 3.35-3.25(m,1H),3.18-3.06(m,1H),2.37-2.26(m,1H),2.05-2.05(m,3H)。
步骤六：(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-氯-1H-苯并[d]咪唑-2-基)-3,5-二氟苯基)吡咯烷-2-酮(10)
室温下向化合物10e(50.0mg,0.172mmol)和吡咯烷-2-酮(8.7mg,0.10mmol)的1,4-二氧六环(3mL)溶液中加入Cs 2CO 3(67.2mg,0.21mmol)、Pd(dba) 2(5.9mg,0.01mmol)和Xantphos(11.9mg,0.02mmol)。然后所得混合物用氮气鼓泡5分钟，混合物在90℃下搅拌12小时。LCMS显示反应完全。将反应液冷却至室温，过滤、减压浓缩滤液。残余物经制备HPLC(柱子：YMC-Actus Triart C18 150*30mm*7μm，乙腈/水(含0.05％氨水)＝47-70％，9分钟)纯化并冻干后得到标题化合物10(13.5mg,产率：26.8％)。
MS(ESI)m/z＝489.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.82-7.73(m,2H),7.66(d,J＝10.8Hz,2H),7.36(dd,J＝2.0,8.8Hz,1H),4.33(br dd,J＝3.2,15.2Hz,1H),4.17(br dd,J＝7.6,15.2Hz,1H),3.92(t,J＝7.2Hz,2H),3.69-3.48(m,3H),3.21(br d,J＝10.0Hz,2H),3.10(br s,1H),3.00(br s,1H),2.60(t,J＝8.0Hz,2H),2.17-2.11(m,2H),1.93(s,3H)。
实施例11
(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-6-氟-5-甲基-1H-苯并[d]咪唑-2-基)-3-氯-5-氟苯基)吡咯烷-2-酮(11)
Figure PCTCN2021112386-appb-000068
步骤一：(S)-1-(2-(((5-氟-4-甲基-2-硝基苯基)氨基)甲基)吗啉代)乙烷-1-酮(11a)
化合物11a的合成步骤参见实施例10的步骤三。其中以1,5-二氟-2-甲基-4-硝基苯替代1-氟-4-氯-2-硝基苯。
MS(ESI)m/z＝312.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.24(br s,1H),8.11-8.04(m,1H),6.53-6.45(m,1H),4.54(br d,J＝13.3Hz,1H),4.07-4.01(m,1H),3.74-3.58(m,3H),3.46-3.26 (m,3H),2.66(dd,J＝10.8,13.1Hz,1H),2.20-2.12(m,6H)。
步骤二：(S)-1-(2-((2-(4-溴-2-氯-6-氟苯基)-6-氟-5-甲基-1H-苯并[d]咪唑-1-基)甲基)吗啉代)乙烷-1-酮(11b)
室温下，向化合物11a(100.0mg,0.32mmol)的乙醇(2mL)和DMSO(2mL)混合溶液中加入4-溴-2-氯-6-氟苯甲醛(83.9mg,0.35mmol)和Na 2S 2O 4(447.4mg,2.57mmol)。所得混合物在90℃下搅拌12小时。LCMS显示原料反应完全。加入水(15mL)淬灭反应并用乙酸乙酯(20mL×3)萃取。合并的有机层经无水硫酸钠干燥，过滤并在减压下浓缩。残余物经C18反相色谱法(乙腈/水(含0.05％NH 3·H 2O)＝10-75％，流速：40mL/min)纯化并冻干后得到标题化合物11b(100.0mg,产率：62.5％)。
MS(ESI)m/z＝498.1[M+H] +。
步骤三：(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-6-氟-5-甲基-1H-苯并[d]咪唑-2-基)-3-氯-5-氟苯基)吡咯烷-2-酮(11)
化合物11的合成步骤参见实施例10的步骤六。其中以化合物11b替代化合物10e。
MS(ESI)m/z＝503.4[M+H] +。
实施例12
(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-氯-6-氟-1H-苯并[d]咪唑-2-基)-3-氯-5-氟苯基)吡咯烷-2-酮(12)
Figure PCTCN2021112386-appb-000069
步骤一：叔丁基(S)-2-(((4-氯-5-氟-2-硝基苯基)氨基)甲基)吗啉-4-羧酸酯(12a)
化合物12a的合成步骤参见实施例10的步骤三。其中以1-氯-2,4-二氟-5-硝基苯替代1-氟-4-氯-2-硝基苯。
1H NMR(400MHz,CDCl 3)δ8.36-8.25(m,2H),6.65(d,J＝11.6Hz,1H),4.09-3.80(m,3H),3.75-3.67(m,1H),3.63-3.53(m,1H),3.43-3.35(m,1H),3.34-3.25 (m,1H),2.99(br s,1H),2.79(br s,1H),1.48(s,9H)。
步骤二：叔丁基(S)-2-(((2-氨基-4-氯-5-氟苯基)氨基)甲基)吗啉-4-羧酸酯(12b)
化合物12b的合成步骤参见实施例10的步骤四。其中以化合物12a替代化合物10c。
1H NMR(400MHz,DMSO-d 6)δ7.81-7.65(m,1H),6.63-6.37(m,1H),4.68(br s,1H),4.40-4.18(m,1H),3.84(br d,J＝12.0Hz,1H),3.76-3.61(m,2H),3.12-3.00(m,1H),2.85(br s,1H),2.53(br s,2H),1.40(d,J＝1.6Hz,9H),1.27-1.20(m,3H)。
步骤三：叔丁基(S)-2-((2-(4-溴-2-氯-6-氟苯基)-5-氯-6-氟-1H-苯并[d]咪唑-1-基)甲基)吗啉-4-羧酸酯(12c)
化合物12c的合成步骤参见实施例10的步骤五。其中以化合物12b替代化合物10d，以4-溴-2-氯-6-氟苯甲醛替代4-溴-2,6-二氟苯甲醛。
MS(ESI)m/z＝578.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.87(d,J＝6.8Hz,1H),7.59-7.55(m,1H),7.40-7.33(m,2H),4.08-3.97(m,2H),3.75(br s,3H),3.62-3.50(m,1H),3.33(br s,1H),2.81(br s,1H),2.47(br t,J＝11.6Hz,1H),0.96(s,9H)。
步骤四：(S)-1-(2-((2-(4-溴-2-氯-6-氟苯基)-5-氯-6-氟-1H-苯并[d]咪唑-1-基)甲基)吗啉代)乙烷-1-酮(12d)
化合物12c的合成步骤参见实施例10的步骤一。其中以化合物12c替代化合物1a。
MS(ESI)m/z＝518.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.90-7.85(m,1H),7.61-7.56(m,1H),7.41-7.32(m,2H),4.50-4.38(m,1H),4.08-4.01(m,2H),3.86-3.79(m,1H),3.55(br d,J＝11.2Hz,2H),3.41-3.32(m,1H),3.24-3.11(m,1H),2.42-2.27(m,1H),2.09(s,3H)。
步骤五：(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-氯-6-氟-1H-苯并[d]咪唑-2-基)-3-氯-5-氟苯基)吡咯烷-2-酮(12)
化合物12的合成步骤参见实施例10的步骤六。其中以化合物12d替代化合物10e。
MS(ESI)m/z＝523.3[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.93-7.87(m,3H),7.78(dd,J＝2.0,12.0Hz,1H),4.38-3.99(m,3H),3.93(t,J＝7.2Hz,2H),3.72-3.44(m,3H),3.33-3.13(m,2H),3.06-2.85(m,1H),2.60(t,J＝8.4Hz,2H),2.13(quin,J＝7.6Hz,2H),1.95(s,3H)。
实施例13
(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-氯-7-氟-1H-苯并[d]咪唑-2-基)-3,5-二氟苯基)吡咯烷-2-酮(13)
Figure PCTCN2021112386-appb-000070
步骤一：(S)-1-(2-(((4-氯-2-氟-6-硝基苯基)氨基)甲基)吗啉代)乙烷-1-酮(13a)
化合物13a的合成步骤参见实施例10的步骤三。其中以5-氯-1,2-二氟-3-硝基苯替代1-氟-4-氯-2-硝基苯。
MS(ESI)m/z＝332.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.05-7.92(m,2H),7.27-7.20(m,1H),4.54-4.40(m,1H),4.05-3.97(m,1H),3.83-3.73(m,1H),3.71-3.60(m,2H),3.60-3.51(m,2H),3.36-3.06(m,1H),2.87-2.55(m,1H),2.12(s,3H)。
步骤二：(S)-1-(2-(((2-氨基-4-氯-6-氟苯基)氨基)甲基)吗啉代)乙烷-1-酮(13b)
化合物13b的合成步骤参见实施例10的步骤四。其中以化合物13a替代化合物10c。
1H NMR(400MHz,CDCl 3)δ6.53-6.45(m,2H),4.42(br d,J＝13.2Hz,1H),4.13(q,J＝7.2Hz,3H),4.00(br d,J＝11.6Hz,1H),3.63-3.44(m,3H),3.36-3.25(m,1H),3.09-2.92(m,2H),2.85-2.53(m,1H),2.09(d,J＝9.2Hz,3H)。
步骤三：(S)-1-(2-((2-(4-溴-2,6-二氟苯基)-5-氯-7-氟-1H-苯并[d]咪唑-1-基)甲基)吗啉代)乙烷-1-酮(13c)
化合物13c的合成步骤参见实施例10的步骤五。其中以化合物13b替代化合物10d。
MS(ESI)m/z＝503.8[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.67-7.60(m,1H),7.33-7.27(m,2H),7.14-7.05(m,1H),4.51(br d,J＝13.2Hz,1H),4.41-4.27(m,2H),3.73-3.58(m,2H),3.28(br t,J＝11.6Hz,1H),3.15-3.03(m,1H),2.81(br t,J＝12.2Hz,1H),2.64-2.53(m,1H),2.34-2.25(m,1H),2.05(s,3H)。
步骤四：(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-氯-7-氟-1H-苯并[d]咪唑-2-基)-3,5-二氟苯基)吡咯烷-2-酮(13)
化合物13的合成步骤参见实施例10的步骤六。其中以化合物13c替代化合 物10e。
MS(ESI)m/z＝507.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.79-7.65(m,3H),7.41(d,J＝11.2Hz,1H),4.51-4.37(m,1H),4.23(br d,J＝13.2Hz,1H),4.11(br dd,J＝8.4,15.2Hz,1H),4.02(br d,J＝13.2Hz,1H),3.90(t,J＝7.2Hz,2H),3.73(br d,J＝12.8Hz,1H),3.63-3.50(m,2H),3.28-3.07(m,1H),3.02-2.72(m,1H),2.59(t,J＝8.0Hz,2H),2.30-2.20(m,1H),2.57-2.07(m,2H),1.93(s,3H)。
实施例14
(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-(甲基-d3)-1H-苯并[d]咪唑-2-基)-3,5-二氟苯基)吡咯烷-2-酮(14)
Figure PCTCN2021112386-appb-000071
步骤一：叔丁基(S)-2-(((4-溴-2-硝基苯基)氨基)甲基)吗啉-4-羧酸酯(14a)
室温下，向化合物1b(2.00g,7.40mmol)的1,4-二氧六环(10mL)溶液中加入4-溴-1-氟-2-硝基苯(1.63g,7.40mmol)和三乙胺(2.0mL,14.80mmol)，然后反应混合物在80℃下搅拌12小时。LCMS显示原料消失完全。反应液直接减压浓缩，得到粗产品经快速硅胶色谱纯化(乙酸乙酯/石油醚＝0-15％,60mL/min)得到标题化合物14a(2.00g,产率：58.4％)。
1H NMR(400MHz,CDCl 3)δ8.25(d,J＝2.4Hz,1H),8.15(br s,1H),7.44(dd,J＝2.4,9.2Hz,1H),6.71(d,J＝9.2Hz,1H),3.96-3.72(m,3H),3.63(tdd,J＝3.2,7.2,10.4Hz,1H),3.55-3.46(m,1H),3.39-3.23(m,2H),2.92(br s,1H),2.71(br s,1H),1.40(s,9H)。
步骤二：叔丁基(S)-2-(((4-(甲基-d 3)-2-硝基苯基)氨基)甲基)吗啉-4-羧酸酯(14b)
室温下向化合物14a(1.10g,2.64mmol)和4,4,5,5-四甲基-2-(甲基-d 3)-1,3,2-二噁硼戊环(1.15g,7.93mmol)的1,4-二氧六环(15mL)和水(5mL)混合溶液中加入 Cs 2CO 3(2.58g,7.93mmol)和Pd(dppf)Cl 2.CH 2Cl 2(58.8mg,0.072mmol)。然后所得混合物用氮气鼓泡5分钟，混合物在氮气氛围中于100℃下搅拌12小时。LCMS显示反应完全。将反应液冷却至室温，加入水(20mL)，用乙酸乙酯(50mL×3)萃取。合并的有机相经无水硫酸钠干燥，过滤并减压浓缩，得到粗产品经快速硅胶色谱纯化(乙酸乙酯/石油醚＝0-20％,35mL/min)得到标题化合物14b(470.0mg,产率：45.2％)。
MS(ESI)m/z＝299.2[M+H-56] +。
1H NMR(400MHz,DMSO-d 6)δ8.09(br t,J＝5.6Hz,1H),7.87(d,J＝2.4Hz,1H),7.39(dd,J＝2.0,8.8Hz,1H),7.04(d,J＝8.8Hz,1H),3.87(br d,J＝11.2Hz,2H),3.70(br d,J＝13.2Hz,1H),3.63-3.50(m,2H),3.47-3.36(m,2H),3.27-3.24(m,1H),2.88(br s,1H),1.39(s,9H)。
步骤三：叔丁基(S)-2-((2-(4-溴-2,6-二氟苯基)-5-(甲基-d 3)-1H-苯并[d]咪唑-1-基)甲基)吗啉-4-羧酸酯(14c)
室温下，向化合物14b(200.0mg,0.56mmol)的乙醇(6mL)和水(2mL)混合溶液中加入4-溴-2,6-二氟苯甲醛(124.7mg,0.56mmol)和Na 2S 2O 4(294.8mg,1.69mmol)。所得混合物在氮气氛围中于80℃下搅拌4小时。LCMS显示原料反应完全。反应液过滤后滤液中加入水(3mL)并用乙酸乙酯(10mL×3)萃取。合并的有机相经无水硫酸钠干燥，过滤并在减压下浓缩得到标题化合物14c(340.0mg,产率：114.7％)。
MS(ESI)m/z＝525.1[M+H] +。
步骤四：(S)-1-(4-(1-((4-乙酰基吗啉-2-基)甲基)-5-(甲基-d3)-1H-苯并[d]咪唑-2-基)-3,5-二氟苯基)吡咯烷-2-酮(14)
室温下向化合物14c(300.0mg,0.57mmol)和吡咯烷-2-酮(48.4mg,0.57mmol)的1,4-二氧六环(8mL)溶液中加入Cs 2CO 3(372.1mg,1.14mmol)、Pd(dba) 2(32.8mg,0.057mmol)和Xantphos(66.1mg,0.11mmol)。然后所得混合物用氮气鼓泡5分钟，在100℃下搅拌2小时。LCMS显示反应完全。待反应液冷却至室温后加入对甲苯磺酸(981.5mg,5.70mmol)，反应混合物在100℃下搅拌1小时，LCMS显示反应完全。反应液冷却至室温后加入甲醇(5mL)，冰水浴下加入三乙胺(1.2mL,8.55mmol)调节pH至8，然后加入乙酸酐(267μL,2.85mmol)并在室温下反应1小时。LCMS显示反应完全，加入水(10mL)并用乙酸乙酯(20mL×3)萃取。合并的有机相经无水硫酸钠干燥，过滤并在减压下浓缩，残余物经制备HPLC(柱子：YMC Triart C18 250*50mm*7μm，乙腈/水(含0.05％氨水)＝12-52％，9分钟)纯化并冻干后得到标题化合物14(90.2mg,产率：33.3％)。
MS(ESI)m/z＝472.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.69-7.58(m,3H),7.49(d,J＝1.2Hz,1H),7.16(dd,J＝1.6,8.4Hz,1H),4.27(br dd,J＝3.6,15.2Hz,1H),4.12(br dd,J＝7.2,15.2 Hz,1H),3.92(t,J＝7.2Hz,2H),3.64(br dd,J＝2.0,11.6Hz,1H),3.54(br s,2H),3.23(br s,2H),3.14-3.09(m,2H),2.60(t,J＝8.0Hz,2H),2.18-2.08(m,2H),1.93(s,3H)。
实施例15
(S)-1-(3-氯-4-(1-((4-(环丙羰基)吗啉-2-基)甲基)-5-甲基-1H-苯并[d]咪唑-2-基)-5-氟苯基)吡咯烷-2-酮(15)
Figure PCTCN2021112386-appb-000072
步骤一：叔丁基(S)-2-((2-(4-溴-2-氯-6-氟苯基)-5-甲基-1H-苯并[d]咪唑-1-基)甲基)吗啉-4-羧酸酯(15a)
化合物15a的合成步骤参见实施例1的步骤五。其中以4-溴-2-氯-6-氟苯甲醛替代4-溴-2,6-二氟苯甲醛。
MS(ESI)m/z＝540.1[M+H+2] +。
步骤二：(R)-1-(3-氯-5-氟-4-(5-甲基-1-(吗啉-2-基甲基)-1H-苯并[d]咪唑-2-基)苯基)吡咯烷-2-酮(15b)
室温下向化合物15a(870.0mg,1.62mmol)和吡咯烷-2-酮(549.7mg,6.46mmol)的1,4-二氧六环(10mL)溶液中加入Cs 2CO 3(1.05g,3.23mmol)、Pd(dba) 2(92.9mg,0.16mmol)和Xantphos(186.8mg,0.32mmol)。然后所得混合物用氮气鼓泡5分钟，在100℃下搅拌4小时。LCMS显示反应完全。待反应液冷却至室温后加入对甲苯磺酸一水合物(3.07g,16.14mmol)，反应混合物在100℃下搅拌1小时，LCMS显示反应完全。加入水(15mL)并用乙酸乙酯(20mL×3)萃取。水相用1N NaOH水溶液调节pH至8并用乙酸乙酯(20mL×3)萃取，合并的有机相经无水硫酸钠干燥，过滤并在减压下浓缩得到标题化合物15b(680.0mg,产率：95.1％)。
MS(ESI)m/z＝443.5[M+H] +。
步骤三：(S)-1-(3-氯-4-(1-((4-(环丙羰基)吗啉-2-基)甲基)-5-甲基-1H-苯并[d]咪唑-2-基)-5-氟苯基)吡咯烷-2-酮(15)
向化合物15b(50.0mg,0.11mmol)的DMF(1mL)溶液中依次加入环丙基甲酸(19.4mg,0.23mmol)、HATU(85.8mg,0.0.23mmol)和N,N-二异丙基乙胺(75μL,0.45mmol)。室温下搅拌1小时，反应液直接经C18反相色谱法(乙腈/水(含0.05％氨水)＝10-75％)纯化并冻干后得到标题化合物15(32.0mg,产率：55.5％)。
MS(ESI)m/z＝469.4[M+H] +。
1H NMR(400MHz,DMSO-d 6,t＝75℃)δ7.87(s,1H),7.77(dd,J＝12.0,2.1Hz,1H),7.60(d,J＝8.3Hz,1H),7.49(s,1H),7.16(dd,J＝8.4,1.6Hz,1H),4.27-4.11(m,2H),4.08(t,J＝5.1Hz,2H),3.99(d,J＝13.5Hz,1H),3.93(t,J＝7.1Hz,2H),3.68(br s,1H),3.56(br s,1H),3.47(dd,J＝7.0,5.1Hz,2H),3.25(t,J＝11.7Hz,1H),2.59(dd,J＝8.5,7.6Hz,2H),2.46(s,3H),2.13(p,J＝7.5Hz,2H),1.08(t,J＝7.0Hz,4H)。
实施例16
(S)-1-(3-氯-5-氟-4-(5-甲基-1-((4-(3,3,3-三氟丙酰)吗啉-2-基)甲基)-1H-苯并[d]咪唑-2-基)苯基)吡咯烷-2-酮(16)
Figure PCTCN2021112386-appb-000073
化合物16的合成步骤参见实施例15的步骤三。其中以3,3,3-三氟丙酸替代环丙基甲酸。
1H NMR(400MHz,DMSO-d 6,t＝75℃)δ7.86(s,1H),7.76(dd,J＝12.0,2.1Hz,1H),7.60(d,J＝8.3Hz,1H),7.49(s,1H),7.16(dd,J＝8.5,1.6Hz,1H),4.41-4.13(m,2H),4.08(t,J＝5.1Hz,2H),3.93(t,J＝7.1Hz,2H),3.78-3.64(m,1H),3.59-3.44(m,5H),3.35-3.16(m,1H),2.59(t,J＝8.1Hz,2H),2.46(s,3H),2.13(p,J＝7.6Hz,2H)。
实施例17
(S)-6-氯-8-氟-7-(5-甲基-1-((4-丙酰吗啉-2-基)甲基)-1H-苯并[d]咪唑-2-基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(17)
Figure PCTCN2021112386-appb-000074
步骤一：4-氯-2-氟-6-硝基苯酚(17a)
冰水浴下，向4-氯-2-氟苯酚(10.00g,68.24mmol)的乙酸(100mL)溶液中缓慢滴加发烟硝酸(4.51g,71.65mmol)，然后反应混合物在冰水浴下搅拌1小时。LCMS显示原料消失完全。在搅拌状态下，反应液直接缓慢倒入水(1.5L)中。搅拌1小时后，抽滤得到固体干燥后得到标题化合物17a(11.00g,产率：84％)。
1H NMR(400MHz,CDCl 3)δ10.38(s,1H),7.94(t,J＝2.4Hz,1H),7.45(dd,J＝2.4,9.6Hz,1H)。
步骤二：2-氨基-4-氯-6-氟苯酚(17b)
室温下，向化合物17a(5.00g,26.10mmol)的四氢呋喃(60mL)、乙醇(60mL)和水(30mL)混合溶液中加入氯化铵(13.96g,261.04mmol)和铁粉(11.69g,208.83mmol)。然后反应混合物在60℃下搅拌2小时。LCMS显示原料消失完全。反应混合物经过滤后滤液减压浓缩，残余物用乙酸乙酯(500mL)分散并过滤，滤液减压浓缩得到标题化合物17b(4.20g,产率：99.6％)。
MS(ESI)m/z＝162.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ6.56-6.49(m,2H),5.03(br s,1H),3.93(br s,2H)。
步骤三：6-氯-8-氟-2H-苯并[b][1,4]噁嗪-3(4H)-酮(17c)
冰水浴下，向化合物17b(4.20g,26.00mmol)的四氢呋喃(50mL)溶液中加入碳酸钾(10.78g,77.99mmol)和氯乙酰氯(3.1mL,38.99mmol)，然后在40℃下搅拌反应15小时。LCMS显示原料消失完全。加入水(100mL)淬灭反应，使用二氯甲烷(100mL×3)萃取，有机相干燥浓缩，粗品经由硅胶柱色谱法(乙酸乙酯/石油醚＝30％,流速：30mL/min)纯化得到标题化合物17c(4.30g,82.0％)。
1H NMR(400MHz,DMSO-d 6)δ11.00(br s,1H),7.10(dd,J＝2.4,10.4Hz,1H),6.74(t,J＝2.0Hz,1H),4.68(s,2H)。
步骤四：6-氯-8-氟-3-羰基-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲醛(17d)
-78℃下，向2,2,6,6-四甲基哌啶(3.8mL,22.32mmol)的无水四氢呋喃(4mL)溶液中滴加2.5M正丁基锂的正己烷溶液(8.9mL,22.32mmol)。滴加完毕后，维持-78℃搅拌20分钟，然后将化合物17c(1.50g,7.44mmol)的无水四氢呋喃(15mL) 溶液缓慢滴入。在-78℃下搅拌3小时后，缓慢滴加N,N-二甲基甲酰胺(1.09g,14.88mmol)，然后缓慢升至室温后继续反应30分钟。TLC(石油醚/乙酸乙酯＝1/1)显示反应完全后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯(50mL×3)萃取，合并的有机相经无水硫酸钠干燥、过滤并浓缩后得到标题化合物17d(600.0mg,35.0％)。
1H NMR(400MHz,DMSO-d 6)δ11.38(br s,1H),10.16(d,J＝0.8Hz,1H),6.85(d,J＝1.6Hz,1H),4.76(s,2H)。
步骤五：叔丁基(S)-2-((2-(6-氯-8-氟-3-羰基-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)-5-甲基-1H-苯并[d]咪唑-1-基)甲基)吗啉-4-羧酸酯(17e)
化合物17e的合成步骤参见实施例14的步骤三。其中以化合物1c替代化合物14b，以化合物17d替代4-溴-2,6-二氟苯甲醛。
MS(ESI)m/z＝531.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ9.81(br s,1H),7.69(s,1H),7.41(dd,J＝2.4,8.4Hz,1H),7.21(d,J＝8.4Hz,1H),6.79(dd,J＝1.2,5.6Hz,1H),4.75-4.71(m,2H),4.12-4.02(m,2H),3.99-3.69(m,3H),3.66-3.56(m,1H),3.41-3.26(m,1H),2.90-2.76(m,1H),2.52(s,3H),2.52-2.44(m,1H),1.43(s,9H)。
步骤六：(S)-6-氯-8-氟-7-(5-甲基-1-((4-丙酰吗啉-2-基)甲基)-1H-苯并[d]咪唑-2-基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(17)
冰水浴下，向化合物17e(182.0mg,0.34mmol)的二氯甲烷(5mL)溶液中，缓慢滴加4M HCl的1,4-二氧六环溶液(0.9mL)，混合物在室温下搅拌4小时。TLC(石油醚/乙酸乙酯＝1/1)显示反应完成。浓缩，残余物溶于二氯甲烷(3mL)中，冰水浴下加入三乙胺(240μL,1.72mmol)和丙酰氯(33μL,0.38mmol)并在室温下反应2小时。TLC(石油醚/乙酸乙酯＝1/1)显示反应完成。加入水(20mL)淬灭反应并用二氯甲烷(20mL×3)萃取。合并的有机层经无水硫酸钠干燥，过滤并在减压下浓缩。残余物用快速硅胶色谱(乙酸乙酯/石油醚＝0-100％)纯化得到化合物17(74.0mg,产率：44.7％)。
MS(ESI)m/z＝487.1[M+H] +。
生物试验
测试例1:体外生物活性评价
FLIPR测定法筛选化合物对hP2X3和hP2X2/3受体的拮抗活性(以钙流信号变化表示化合物对离子通道的作用)。
1、实验仪器及材料
Figure PCTCN2021112386-appb-000075
Figure PCTCN2021112386-appb-000076
2、实验步骤
将稳定转染hP2X3和hP2X2/3受体的1321N1细胞(贴壁细胞)消化，离心后用铺板培养基(DMEM+10％DFBS)重悬并计数，调整细胞到2*10 5个细胞/mL，在384-孔检测板中每孔铺50μL细胞，置于5％CO 2、37℃培养箱中培养16-24小时。用DMSO配制180倍所需浓度供试化合物(20mM DMSO储备液)，每孔取500nL加到384-孔化合物板中，补充30μL FLIPR缓冲液(含1.26mM Ca 2+的1*HBSS+2mM CaCl 2+20mM HEPES)，振摇20-40min以混匀。用FLIPR缓冲液配制3倍所需浓度激动剂α,β-meATP(hP2X3细胞需终浓度500nM，hP2X2/3细胞需终浓度1000nM)，每孔加35μL激动剂到另一块384-孔化合物板中。取出铺好培养16-24小时的细胞板，吸去细胞上清液，每孔加入30μL染料(
Figure PCTCN2021112386-appb-000077
钙4检测试剂盒，FLIPR缓冲液稀释)，孵育1小时。向每孔细胞中加15μL化合物(FLIPR仪器加样)，15分钟后，每孔加22.5μL激动剂，检测荧光信号(激发光波长470nm-495nm，发射光波长515nm-575nm)。取信号峰值和谷值的差值作为基础数据，以阳性药最高浓度数据作为100％抑制率，DMSO数据作为0％抑制率，在软件Graphpad Prism 6上拟合化合物的抑制效应曲线并计算IC 50值。
表1.本公开化合物对hP2X3和hP2X2/3受体的半数抑制浓度(IC 50)
化合物编号 hP2X3(IC 50,nM) hP2X2/3(IC 50,nM)
MK-7264 35.4 116.2
1 36.8 5566
2 105.0 18990
3 41.2 1805
4 31.6 1927
5 100.4 NT
6 >10000 NT
7 5843 NT
8 >10000 NT
9 75.8 30270
10 54.1 7407
11 79.4 NT
12 87.7 NT
13 765.9 NT
14 33.0 NT
15 85.1 NT
16 70.5 NT
17 45.3 3501
NT:Not Tested(未检测)。
测试例2:CYP抑制实验
使用150个供体混合人肝微粒体(购自Corning,货号452117)评估人主要5个CYP亚型(CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4/5)的代表性底物代谢反应。通过液相色谱串联质谱(LC/MS/MS)测定不同浓度待测化合物对非那西丁(CYP1A2)、双氯芬酸钠(CYP2C9)、S-美芬妥英(CYP2C19)、丁呋洛尔盐酸盐(CYP2D6)、咪达唑仑(CYP3A4/5)代谢反应的影响。
将30μM非那西丁、10μM双氯芬酸钠、35μM S-美芬妥英、5μM丁呋洛尔盐酸盐、3μM咪达唑仑、1mM NADPH、待测化合物(浓度分别为0.1、0.3、1、3、10、30μmol/L)或阳性化合物或空白对照与混合人肝微粒体(0.2mg/mL)的反应体系200μL(100mmol/L磷酸盐缓冲液，pH 7.4，含体积比分别为0.3％的DMSO、0.6％的乙腈、0.1％的甲醇)在37℃孵育5分钟。然后加入200μL含3％甲酸及40nM内标维拉帕米的乙腈溶液，4000rpm离心50分钟。置于冰上冷却20分钟，再4000rpm离心20分钟析出蛋白。取200μL上清液进行LC/MS/MS分析。
峰面积根据色谱图计算。残余活性比例(％)用如下公式进行计算：
峰面积比例＝代谢产物峰面积/内标峰面积
残余活性比例(％)＝待测化合物组的峰面积比例/空白组的峰面积比例
CYP半数抑制浓度(IC 50)通过Excel XLfit 5.3.1.3计算得到。
测得的CYP半数抑制浓度(IC50)数值见下表。
表2.本公开部分化合物对CYP的半数抑制浓度(IC 50)
Figure PCTCN2021112386-appb-000078
测试例3:人肝细胞体外代谢稳定性检测
利用LC/MS/MS测定反应体系中的化合物浓度，以此来计算待测化合物的固有清除率，并评估在人肝细胞中的体外代谢稳定性。
将247.5μL 1×10 6细胞/mL的人肝细胞(购自BioreclamationIVT，货号S01205)混合液和2.5μL 100μM的待测化合物或阳性对照加入孵育板起始反应。以37℃和600rpm进行孵育。分别在0.5，5，15，30，45，60，80，100和120分钟转移20μL孵育体系到终止板上。之后用涡旋混匀2分钟。以4000rpm的速度将终止板离心20分钟。转移每个化合物的上清液40μL至96孔进样板中，之后加入160μL纯水稀释样品。
所得样品由离子色谱图定量。根据待测化合物或阳性对照的峰面积来计算残余率。斜率k使用Microsoft Excel由剩余率的自然对数值对孵育时间的线性回归测定。
固有清除率(in vitro CL int，μL/min/10 6细胞)根据下列等式由斜率值计算：
in vitro CL int＝kV/N
V＝孵育体积(0.25mL)；
N＝每个孔的细胞数(0.25×10 6细胞)
测得的人肝细胞固有清除率值见表3。
表3.本公开部分化合物人肝细胞固有清除率
Figure PCTCN2021112386-appb-000079
Figure PCTCN2021112386-appb-000080
测试例4：Caco-2渗透性实验
通过Caco-2细胞模型利用液相色谱串联质谱(LC/MS/MS)测定分析药物的表观渗透系数(P app)。
测定药物从顶端到基底端的转运速率。装有密度为6.86×10 5细胞/cm2的Caco-2细胞(购自ATCC)的Transwell(购自康宁公司)小室顶端加入108μL含10μM待测化合物的HBSS(25mM HEPES，pH 7.4)，同时立即取出8μL样品到已加有72μL HBSS(25mM HEPES，pH 7.4)和240μL的乙腈溶液(含有100nM阿普唑仑，咖啡因200nM和100nM甲苯磺丁脲)的新的96孔板中作为初始加药端样品(A-B)，以1000转/分的转速涡旋10分钟，基底端加入300μL HBSS(25mM HEPES，pH 7.4)。
测定药物从基底端到顶端的转运速率。加308μL的含10μM待测化合物的HBSS(25mM HEPES，pH 7.4)到基底端的板孔中，同时立即取出8μL样品到已加有72μL HBSS(25mM HEPES，pH 7.4)和240μL的乙腈溶液(含有100nM阿普唑仑，咖啡因200nM和100nM甲苯磺丁脲)的新的96孔板中作为初始加药端样品(B-A)，以1000转/分的转速涡旋10分钟，顶端加入100μL HBSS(25mM HEPES，pH 7.4)。
顶端到基底端和基底端到顶端需同时进行测试。
在转运周期结束后，从给药端(A-B流向的顶端和B-A流向的基底端)取8μL样品到72μL HBSS(25mM HEPES，pH 7.4)和240μL的乙腈溶液(含有100nM阿普唑仑，咖啡因200nM和100nM甲苯磺丁脲)中，置于新的96孔板中。从A-B流向的基底端和B-A流向的顶端直接取80μL液体加240μL的(含有100nM阿普唑仑，咖啡因200nM和100nM甲苯磺丁脲)乙腈溶液一起加到新的96孔板中。以1000转/分的转速涡旋10分钟。样品以4000转/分的转速离心30分钟。将100μL上清转移到新的96孔板上。所有样品加100μL纯水，LC-MS/MS分析。
使用Microsoft Excel计算数据，峰面积根据色谱图计算。表观渗透系数(Papp)的单位是cm/s，用如下公式进行计算：
Figure PCTCN2021112386-appb-000081
Papp为表观渗透率(cm/s×10 -6)；
dQ/dt为药物传输速率(pmol/s)；
A为膜的表面积(cm 2)；
D 0为初始供给端药物浓度(nM；pmol/立方厘米)。
流出比可由下式确定：
Figure PCTCN2021112386-appb-000082
Papp(B-A)为基底端向顶端方向的表观渗透系数；
Papp(A-B)为顶端向基底端方向的表观渗透系数。
测得的Caco-2细胞表观渗透系数值见表4。
表4
Figure PCTCN2021112386-appb-000083
注：
Figure PCTCN2021112386-appb-000084
BLU-5937。
测试例5：大鼠体内药代动力学实验
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予本公开化合物后不同时刻血浆中的药物浓度。研究本公开化合物在大鼠体内的药代动力学行为，评价其药动学特征。
1、试验方案
1.1试验药品
化合物4和BLU-5937。
1.2试验动物
6-8周龄、SPF级、雄性、健康SD大鼠，每组3只。
1.3药物配制
灌胃给药：称取一定量药物，加0.5％的羟丙甲纤维素、0.1％的吐温80和99.4％体积的水配制成1mg/mL的白色悬浊液。
1.4给药
SD大鼠禁食过夜后灌胃给药，化合物4和BLU-5937给药剂量为5mg/kg。
2、操作
大鼠灌胃给药本公开化合物，给药后0.25、0.5、1、2、4、8、24小时由颈静脉采血0.2mL，置于含EDTA-K2的试管中，4℃、4000转/分钟离心5分钟分离血浆，于-75℃保存。
测定不同浓度的药物灌胃给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆50μL，加入内标地塞米松(50ng/mL)的乙腈溶液200μL，涡旋混合30秒，4℃、4700转/分钟离心15分钟，血浆样品取上清液加水稀释三倍，取2.0μL进行LC/MS/MS分析。
3、药代动力学参数结果
本公开部分化合物的大鼠药代动力学参数如下：
表5
Figure PCTCN2021112386-appb-000085

Claims (21)

  1. 式(I)化合物或其可药用盐、或其异构体，
    Figure PCTCN2021112386-appb-100001
    其中，R 1选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
    R 2各自独立地选自氢、氘、卤素、C 1-C 6羟烷基、任选地被卤素或氘取代的C 1-C 6烷基和任选地被卤素或氘取代的C 1-C 6烷氧基；
    R 3和R 4各自独立地选自氢、卤素和任选地被卤素取代的C 1-C 4烷基，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基，或者相邻碳原子上的R 3和R 4一起形成任选被卤素取代的C 3-C 8环烷烃；
    R 5选自任选地被卤素或氰基取代的C 1-C 6烷基、任选地被卤素或氰基取代的C 3-C 6环烃基、任选地被卤素或氰基取代的杂环基、任选地被卤素或氰基取代的C 1-C 6烷氧基和任选地被烷基取代的氨基；
    R 6各自独立地选自氢、氘、卤素、氰基、环丙基和任选地被卤素或氘取代的C 1-C 6烷基；
    R 7和R 8各自独立地选自：
    a)氢、氘、卤素、氰基、氨基、羟基、任选地被卤素取代的C 1-C 6烷基、砜、亚砜、磺酰胺、亚磺酰胺、C 1-3的羧基和任选地被卤素取代的C 1-C 6烷氧基；
    b)
    Figure PCTCN2021112386-appb-100002
    p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 6烷基、C 1-C 6烷氧基和C 3-C 8环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被选自卤素、羟基、氰基、C 1-C 6卤代烷基和C 1-C 6烷基的一个或多个取代基取代；R’选自氢、C 1-C 6烷基、C 3-C 8环烃基、芳基和杂芳基；并且在
    Figure PCTCN2021112386-appb-100003
    中，当p为0，R 9为氢 时，R 10不为甲基；当p为0，R 9为甲基时，R 10不为氢；
    c)
    Figure PCTCN2021112386-appb-100004
    d)杂环基和杂芳基，所述的杂环基和杂芳基各自任选地被选自氧代、卤素、羟基、羰基、C 1-C 6烷基和氰基的一个或多个取代基取代，所述的C 1-C 6烷基任选地被一个或多个卤素取代；和
    e)
    Figure PCTCN2021112386-appb-100005
    其中，R 11选自C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、C 3-C 8环烃基、杂环基、C 1-C 6氰代烷基、C 3-C 8环烃基氧基和任选被C 1-C 6烷基取代的氨基；或者
    R 7和R 8与其共同连接的原子一起形成任选被取代的芳香或非芳香杂环；
    X选自氧原子、-NH-和亚甲基，所述亚甲基任选地被选自卤素、C 3-C 8环烃基、C 3-C 6亚环烃基和C 1-C 6烷基的一个或多个取代基取代；
    m为1-3的整数；且
    n为1-4的整数。
  2. 根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体，其中，R 7和R 8各自独立地选自：
    a)氢、氘、卤素、氰基、氨基、砜、磺酰胺、亚磺酰胺和被一个或多个卤素取代的C 1-C 3烷基；
    b)
    Figure PCTCN2021112386-appb-100006
    p选自0、1和2，R 9和R 10各自独立地选自氢、C 1-C 3烷基、C 1-C 3烷氧基和C 3-C 6环烃基，或者R 9和R 10与其共同连接的氮原子一起形成4-6元杂环基，所述杂环基任选地被选自卤素、羟基和C 1-C 3烷基的一个或多个取代基取代；R’选自氢、C 1-C 3烷基、C 3-C 6环烃基、芳基和杂芳基；并且在
    Figure PCTCN2021112386-appb-100007
    中，当p为0时，R 9和R 10的组合不为氢和甲基；
    c)
    Figure PCTCN2021112386-appb-100008
    d)4-6元杂环基和杂芳基，所述的杂环基和杂芳基各自任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基取代，所述的C 1-C 3烷基任选地被一个或多个卤素取代；和
    e)
    Figure PCTCN2021112386-appb-100009
    其中，R 11选自C 1-C 3烷基、C 1-C 3烷氧基、5-6元芳基或杂芳基、3-8元环烃基、3-8元杂环基、C 1-C 3氰代烷基、C 3-C 6环烃基氧基和任选被C 1-C 3烷基取代的氨基。
  3. 根据权利要求1或2所述的式(I)化合物或其可药用盐、或其异构体，其中，
    R 7为4-6元杂环基或杂芳基，所述的杂环基或杂芳基任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基取代，所述的C 1-C 3烷基任选地被一个或多个卤素取代；且
    R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基。
  4. 根据权利要求1-3任一项所述的式(I)化合物或其可药用盐、或其异构体，其中，
    R 7为4-6元杂环基，所述杂环基包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环基任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基取代，所述的C 1-C 3烷基任选地被一个或多个卤素取代，进一步地，R 7优选5元杂环基，所述杂环基包含-NH-C(＝O)-，所述杂环基任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基取代，所述的C 1-C 3烷基任选地被一个或多个卤素取代。
  5. 根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体，其中，
    R 7和R 8与其共同连接的原子一起形成3-12元芳香或非芳香杂环，所述杂环为单环或双环，所述杂环任选被选自C 1-C 6烷基酰胺、卤素、氧代、任选地被卤素取代的C 1-C 6烷基和C 1-C 6烷氧基的一个或多个取代基取代；进一步地，R 7和R 8优选与其共同连接的原子一起形成3-12元非芳香杂环，所述杂环为单环或双环，所述杂环包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环任选被选自C 1-C 6烷基酰胺、卤素、氧代、任选地被卤素取代的C 1-C 6烷基和C 1-C 6烷氧基的一个或多个取代基 取代；R 7和R 8更优选与其共同连接的原子一起形成4-8元非芳香杂环，所述杂环为单环或双环，所述杂环包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环任选被选自C 1-C 3烷基酰胺、卤素、氧代、任选地被卤素取代的C 1-C 3烷基和C 1-C 3烷氧基的一个或多个取代基取代。
  6. 根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体，其中，
    R 5为任选地被卤素或氰基取代的C 1-C 6烷基或任选地被卤素或氰基取代的C 1-C 6烷氧基；
    R 6各自独立地选自氢、氘、卤素和氰基；且
    n为1-4的整数。
  7. 根据权利要求1或6所述的式(I)化合物或其可药用盐、或其异构体，其中，
    R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
    R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
    R 3和R 4各自独立地为氢或卤素，或者R 3和R 4与其共同连接的碳原子一起形成任选地被卤素取代的C 3-C 6亚环烃基；
    R 5为C 1-C 6烷基或C 1-C 6烷氧基；
    R 6各自独立地选自氢、氘、卤素和氰基；
    m为1-3的整数；且
    n为1-4的整数。
  8. 根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体，其中，
    R 7为任选地被选自甲基、氟原子、氯原子、卤代甲基和氰基的一个或多个取代基取代的以下基团：
    Figure PCTCN2021112386-appb-100010
    Figure PCTCN2021112386-appb-100011
    且
    R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基。
  9. 根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体，其中，
    R 7和R 8与其共同连接的原子一起形成杂环A
    Figure PCTCN2021112386-appb-100012
    杂环A选自以下结构：
    Figure PCTCN2021112386-appb-100013
    R 6各自独立地选自氢、氘、卤素和氰基；
    R 12各自独立地选自卤素、C 1-C 3烷基和C 3-C 6亚环烃基，或者相邻的R 12一起形成环，所述的环任选地被一个或多个卤素或C 1-C 3烷基取代；
    n选自1-3的整数；且
    q为0-6的整数。
  10. 根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体，其中，
    R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
    R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
    R 3和R 4各自独立地为氢或卤素，或者R 3和R 4与其共同连接的碳原子一起形 成任选地被卤素取代的C 3-C 6亚环烃基；
    R 5为C 1-C 6烷基或C 1-C 6烷氧基；
    R 7和R 8与其共同连接的原子一起形成杂环A
    Figure PCTCN2021112386-appb-100014
    杂环A选自以下结构：
    Figure PCTCN2021112386-appb-100015
    R 6各自独立地选自氢、氘、卤素和氰基；
    m为1-3的整数；且
    n为1-3的整数。
  11. 根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体，其为
    Figure PCTCN2021112386-appb-100016
    其中，R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
    R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
    R 5为C 1-C 3烷基或C 1-C 3烷氧基；
    R 6a和R 6b各自独立地选自氢、氘、氯原子、氟原子和氰基；
    R 7为4-6元杂环基，所述杂环基包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环基任选地被选自氧代、卤素、羟基、羰基、C 1-C 3烷基和氰基的一个或多个取代基 取代，所述的C 1-C 3烷基任选地被一个或多个卤素取代；
    R 8选自氢、氘、卤素、氰基和被一个或多个卤素取代的C 1-C 3烷基；且
    m为1-3的整数。
  12. 根据权利要求11所述的式(I-1)化合物或其可药用盐、或其异构体，其中，
    R 7为任选地被选自甲基、氟原子、氯原子、卤代甲基和氰基的一个或多个取代基取代的以下基团：
    Figure PCTCN2021112386-appb-100017
    且
    R 8选自氢、氘、卤素和氰基。
  13. 根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体，其为
    Figure PCTCN2021112386-appb-100018
    其中，R 1选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
    R 2各自独立地选自氢、氘、任选地被卤素或氘取代的C 1-C 3烷基和卤素；
    R 5为C 1-C 3烷基或C 1-C 3烷氧基；
    R 6a和R 6b各自独立地选自氢、氘、氯原子、氟原子和氰基；
    R 7和R 8与其共同连接的原子一起形成4-8元非芳香杂环，所述杂环为单环或 双环，所述杂环包含-NH-C(＝O)-或者-NH-S(＝O) 2-，所述杂环任选被选自C 1-C 3烷基酰胺、卤素、氧代、任选地被卤素取代的C 1-C 3烷基和C 1-C 3烷氧基的一个或多个取代基取代；且
    m为1-3的整数。
  14. 根据权利要求13所述的式(I-1)化合物或其可药用盐、或其异构体，其中，
    R 7和R 8与其共同连接的原子一起形成杂环A
    Figure PCTCN2021112386-appb-100019
    杂环A选自以下结构：
    Figure PCTCN2021112386-appb-100020
    R 6a和R 6b各自独立地选自氢、氘、氯原子和氟原子；
    R 12各自独立地选自卤素、C 1-C 3烷基和C 3-C 6亚环烃基，或者相邻的R 12一起形成环，所述的环任选地被一个或多个卤素或C 1-C 3烷基取代；且
    q为0-6的整数。
  15. 根据权利要求14所述的式(I-1)化合物或其可药用盐、或其异构体，其中，
    R 7和R 8与其共同连接的原子一起形成杂环A
    Figure PCTCN2021112386-appb-100021
    杂环A选自以下结构：
    Figure PCTCN2021112386-appb-100022
    且
    R 6a和R 6b各自独立地选自氢、氘、氯原子和氟原子。
  16. 根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体，其为
    Figure PCTCN2021112386-appb-100023
    Figure PCTCN2021112386-appb-100024
    Figure PCTCN2021112386-appb-100025
  17. 一种制备根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体的方法，包括如下步骤：
    Figure PCTCN2021112386-appb-100026
    式(I-a)所示的化合物与式(I-b)所示化合物在碱性条件下反应得到式(I-c)所示化合物；式(I-c)所示化合物经还原反应得到式(I-d)所示化合物；式(I-d)所示化合物与式(I-e)所示化合物在酸性条件下经关环反应得到式(I)所示化合物；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、X、m和n的定义如权利要求1所述； 且
    Y选自卤素、磺酰基和亚磺酰基。
  18. 一种制备根据权利要求1所述的式(I)化合物或其可药用盐、或其异构体的方法，包括如下步骤：
    Figure PCTCN2021112386-appb-100027
    式(I-a)所示的化合物与式(I-b)所示化合物在碱性条件下反应得到式(I-c)所示化合物；式(I-c)所示化合物经还原反应得到式(I-d)所示化合物；式(I-d)所示化合物与式(I-f)所示化合物在酸性条件下经关环反应得到式(I-g)所示化合物；式(I-g)所示化合物在催化剂作用下反应得到式(I)所示化合物；
    所述催化剂选自钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1'-双(二苄基磷)二氯二戊铁钯、三(二亚苄基丙酮)二钯或、2-双环己基膦-2',6'-二甲氧基联苯、[1,1'′-双(二-叔丁基膦基)二茂铁]二氯合钯(II)、碘化亚铜、溴化亚铜、氯化亚铜、和三氟甲磺酸铜；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、X、m、和n的定义如权利要求1所述；且
    Y、和Z各自独立地选自卤素、磺酰基和亚磺酰基。
  19. 一种药物组合物，包含根据权利要求1-16中任一项所述的化合物或其可药用盐、或其异构体，和至少一种药学上可接受的载体、稀释剂或者赋形剂。
  20. 根据权利要求1-16中任一项所述的化合物或其可药用盐、或其异构体，或者权利要求19所述的药物组合物在制备治疗与P2X3活性相关的疾病的药物中的用途。
  21. 根据权利要求1-16中任一项所述的化合物或其可药用盐、或其异构体，或者权利要求19所述的药物组合物在制备治疗疾病的药物中的用途，所述疾病选自疼痛、泌尿道疾病和咳嗽。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023151660A1 (zh) * 2022-02-11 2023-08-17 江苏恒瑞医药股份有限公司 一种p2x3受体拮抗剂的结晶形式及其制备方法
WO2023151658A1 (zh) * 2022-02-11 2023-08-17 江苏恒瑞医药股份有限公司 一种p2x3受体拮抗剂的可药用盐及其制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005095359A1 (en) 2004-03-05 2005-10-13 F. Hoffmann-La Roche Ag Diaminopyrimidines as p2x3 and p2x2/3 antagonists
CN102741245A (zh) * 2009-11-18 2012-10-17 阿斯利康(瑞典)有限公司 苯并咪唑化合物及其用途
WO2012158117A1 (en) * 2011-05-17 2012-11-22 Astrazeneca Ab Combination therapies for treating pain
CN108904507A (zh) * 2018-02-11 2018-11-30 赖英杰 P2x3受体调节剂苯并咪唑化合物在制备抗呼吸疾病药物中的应用
WO2019064079A2 (en) * 2017-09-18 2019-04-04 Bellus Health Cough Inc. SELECTIVE MODULATORS OF P2X3
WO2020135771A1 (zh) * 2018-12-29 2020-07-02 武汉朗来科技发展有限公司 杂环类化合物、中间体、其制备方法及应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105246888B (zh) * 2013-01-31 2017-09-05 尼奥迈德研究所 咪唑并吡啶化合物及其用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005095359A1 (en) 2004-03-05 2005-10-13 F. Hoffmann-La Roche Ag Diaminopyrimidines as p2x3 and p2x2/3 antagonists
CN102741245A (zh) * 2009-11-18 2012-10-17 阿斯利康(瑞典)有限公司 苯并咪唑化合物及其用途
WO2012158117A1 (en) * 2011-05-17 2012-11-22 Astrazeneca Ab Combination therapies for treating pain
WO2019064079A2 (en) * 2017-09-18 2019-04-04 Bellus Health Cough Inc. SELECTIVE MODULATORS OF P2X3
CN108904507A (zh) * 2018-02-11 2018-11-30 赖英杰 P2x3受体调节剂苯并咪唑化合物在制备抗呼吸疾病药物中的应用
WO2020135771A1 (zh) * 2018-12-29 2020-07-02 武汉朗来科技发展有限公司 杂环类化合物、中间体、其制备方法及应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4198034A4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023151660A1 (zh) * 2022-02-11 2023-08-17 江苏恒瑞医药股份有限公司 一种p2x3受体拮抗剂的结晶形式及其制备方法
WO2023151658A1 (zh) * 2022-02-11 2023-08-17 江苏恒瑞医药股份有限公司 一种p2x3受体拮抗剂的可药用盐及其制备方法

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